HIV integrase inhibitors

ABSTRACT

The present invention relates to the inhibition of HIV integrase, and to the treatment of AIDS or ARC by administering compounds of the formula  
                 
 
     wherein R 1  is C 1 -C 4  alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2  alkylene, aryloxy-C 1 -C 2  alkylene, alkoxy-CC(O)—, wherein R 1  is optionally substituted from 1-3 times with halo, C 1 -C 2  alkyl or C 1 -C 2  alkoxy, or R 1  is H; R 2  is H or C 1 -C 4  alkyl;  
     R 3  is H, C 1 -C 4  alkyl or phenyl-C 0 -C 2  alkylene which is optionally substituted with 1-3 R 5 ; R 4a  is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4  alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein  
     R 4a  is optionally substituted with 1-3 R 5 ; and wherein  
     each R 5  is independently selected from H, halo, C 1 -C 4  alkyl, C 1 -C 4  alkenyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—, wherein R 6  is H, halo; Z is a bond or a substituted or unsubstituted C 1 -C 4  alkylene group; and  
     B 2  is

RELATED APPLICATIONS

[0001] This is a non-provisional application which claims the benefit ofU.S. Provisional Application No. 60/211,900 filed Jun. 16, 2000.

BACKGROUND

[0002] Human immunodeficiency virus (HIV) has been identified as theetiological agent responsible for acquired immune deficiency syndrome(AIDS), a fatal disease characterized by destruction of the immunesystem and the inability to fight off life threatening opportunisticinfections. Recent statistics (UNAIDS: Report on the Global HIV/AIDSEpidemic, December 1998), indicate that as many as 33 million peopleworldwide are infected with the virus. In addition to the large numberof individuals already infected, the virus continues to spread.Estimates from 1998 point to close to 6 million new infections in thatyear alone. In the same year there were approximately 2.5 million deathsassociated with HIV and AIDS.

[0003] There are currently a number of antiviral drugs available tocombat the infection. These drugs can be divided into three classesbased on the viral protein they target and their mode of action. Inparticular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavirare competitive inhibitors of the aspartyl protease expressed by HIV.Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavirare nucleoside reverse transcriptase inhibitors that behave as substratemimics to halt viral cDNA synthesis. The non-nucleoside reversetranscriptase inhibitors, nevaripine, delavaridine and efavirenz inhibitthe synthesis of viral cDNA via a non-competitive (or uncompetitive)mechanism. Used alone these drugs are effective in reducing viralreplication. The effect is only temporary as the virus readily developsresistance to all known agents. However, combination therapy has provenvery effective at both reducing virus and suppressing the emergence ofresistance in a number of patients. In the US, where combination therapyis widely available, the number of HIV-related deaths has declined(Palella, F J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Furher,J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med.1998, 338, 853).

[0004] Unfortunately, not all patients are responsive and a large numberfail this therapy. In fact, approximately 30-50% of patients ultimatelyfail combination therapy. Treatment failure in most cases is caused bythe emergence of viral resistance. Viral resistance in turn is caused bythe rapid turnover of HIV-l during the course of infection combined witha high viral mutation rate. Under these circumstances incomplete viralsuppression caused by insufficient drug potency, poor compliance to thecomplicated drug regiment as well as intrinsic pharmacological barriersto exposure provides fertile ground for resistance to emerge. Moredisturbing are recent findings which suggest that low-level replicationcontinues even when viral plasma levels have dropped below detectablelevels (<50 copies/ml) (Carpenter, C. C. J.; Cooper, D. A.; Fischl, M.A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.;Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.;Saag, M. S.; Schecter, M.; Schoolery, R. T.; Thompson, M. A.; Vella, S.;Yeni, P. G.; Volberding, P. A. JAMA 2000, 283, 381). Clearly there is aneed for new antiviral agents, preferably targeting other viral enzymesto reduce the rate of resistance and suppress viral replication evenfurther.

[0005] HIV expresses three enzymes, reverse transcriptase, an apartylprotease and integrase, all of which are potential antiviral targets forthe development of drugs for the treatment of AIDS. However, integrasestands out as being the only viral enzyme not targeted by currenttherapy. The integrase enzyme is responsible for insertion of the viralcDNA into the host cell genome, which is critical step in the viral lifecycle. There are a number of discrete steps involved in this processincluding processing of the viral cDNA by removal of two bases from each3′-terminus and joining of the recessed ends to the host DNA. Studieshave shown that in the absence of a functional integrase enzyme HIV isnot infectious. Therefore, an inhibitor of integrase would be useful asa therapy for AIDS and HIV infection.

[0006] A number of inhibitors of the enzyme have been reported. Theseinclude, nucleotide-based inhibitors, known DNA binders, catechols andhydrazide containing derivatives (Nemati, N.; Sundar, S.; Pommier, Y.,Drug Disc. Today, 1997, 2, 487). However, no clinically active compoundhas resulted from these leads.

[0007] Thus, what is needed is a clinically effective inhibitor of theHIV integrase enzyme.

SUMMARY OF THE INVENTION

[0008] The present invention relates to compounds of Formula I, orpharmaceutically acceptable salts or solvates thereof.

[0009] In Formula I,

[0010] R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical,aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂alkoxy, or R¹ is H;

[0011] R² is H or C₁-C₄ alkyl;

[0012] R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionallysubstituted with 1-3 R⁵;

[0013] R⁴ is carbocylic radical, heterocyclic radical, aryloxy,aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ isoptionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³are each H, R4 is not unsubstituted phenyl, o-methoxy phenyl ornaphthalen-1-yl;

[0014] each R⁵ is independently selected from H, halo, C₁-C₄ alkyl,C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy,R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—, wherein R⁶ is H, halo,

[0015] Z is a bond or a substituted or unsubstituted C₁-C₄ alkylenegroup;

[0016] B¹ is selected from the group consisting of

[0017] R⁷ is H or C₁-C₄ alkyl.

[0018] The present invention also relates to a method of inhibiting HIVintegrase by administering to a patient an effective amount of acompound of Structural Formula Ia, or a pharmaceutically salt, solvateor prodrug thereof.

[0019] In Formula Ia, Z, R¹, R², R³, R⁵, R⁶ and R⁷ are as defined forFormula I, whereas R^(4a) is carbocylic radical, heterocyclic radical,aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, whereinR^(4a) optionally substituted with 1-3 R⁵; and wherein B² is

[0020] The present invention further relates to a method of treating apatients infected by the HIV virus, or of treating AIDS or ARC, byadministering to the patient an effective amount of a compound ofStructural Formula Ia, or a pharmaceutically salt, solvate or prodrugthereof.

[0021] Another embodiment includes a pharmaceutical composition, usefulfor inhibiting HIV integrase, or for treating patients infected with theHIV virus, or suffering from AIDS or ARC, which comprises atherapeutically effective amount of one or more of the compounds ofFormula Ia, including pharmaceutically acceptable salts, solvates orprodrugs thereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0022] In the present invention, unless otherwise specified thefollowing definitions apply.

[0023] The numbers in the subscript after the symbol “C” define thenumber of carbon atoms a particular group can contain. For example,“C₁-C₆” means a substituent containing from one to six carbon atoms.

[0024] As used herein, the term “alkyl” means a saturated, straightchain or branched monovalent hydrocarbon radical having the statednumber of carbon atoms. Examples of such alkyl radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and,where indicated, higher homologs and isomers such as n-pentyl, n-hexyl,2-methylpentyl and the like. Haloalkyl refers to an alkyl radical thatis substituted with one or more halo radicals, such as trifluoromethyl.

[0025] The term “alkenyl” means a partially-saturated, straight chain orbranched monovalent hydrocarbon radical having the stated number ofcarbon atoms and is typified by groups such as vinyl, crotonyl andisopentyl.

[0026] The term “alkylene” means a bivalent straight chain alkyl radicalhaving the stated number of carbon atoms such as methylene,1,2-ethanediyl, 1,3-propanediyl and 1,4-butanediyl.

[0027] A preferred substituent for Z, when Z is a substituted C₁-C₄alkylene group, is a hydroxyl group.

[0028] The term “alkoxy” means any of methoxy, ethoxy, n-propoxy,isopropoxy and the like.

[0029] “Halo” means chloro, bromo, iodo or fluoro radicals.

[0030] The term “carbocyclic radical” refers to radicals derived frommonocyclic or polycyclic, saturated or unsaturated, 3-16 memberedorganic nucleus whose ring forming atoms are solely carbon atoms.Typical carbocyclic radicals include aryl, and fused carbocylic ringsystems.

[0031] “Aryl” means aromatic hydrocarbon having from six to ten carbonatoms; examples include phenyl and naphthyl, indenyl, azulenyl,fluorenyl and anthracenyl.

[0032] “Fused carbocyclic ring system” means an aromatic ornon-aromatic, 5-8 membered ring which is optionally fused with one ormore 5-6 membered rings. These fused 5-6 membered rings include aromaticgroups, such as phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl,fluorenyl and anthracenyl, and non-aromatic rings such as cyclopentyl,cyclohexyl and cycloheptyl. Fused ring systems include, for example,dibenzoannulene, naphthylene, tetrahydronaphthylene and indanylene.

[0033] The term “heterocyclic radical” refers to radicals derived frommonocyclic or polycyclic, saturated or unsaturated, heterocyclic nucleihaving 5-16 ring atoms and containing 1 to 3 heteroatoms selected fromthe group consisting of nitrogen, oxygen or sulfur. Typical heterocyclicradicals include heteroaryl, heterocycloalkyl and fused heterocylic ringsystems.

[0034] “Heteroaryl” means a five- or six-membered aromatic ringcontaining at least one and up to four non-carbon atoms selected fromoxygen, sulfur and nitrogen. Examples of heteroaryl, as defined for R₁,include 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl,2-thienyl, 3-thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl and1,3,5-trithianyl. Examples of a heteroaryl group, as defined for R₄,include thienyl, thiazolyl, pyradazinyl, pyrimidinyl, pyrrolyl andoxazolyl.

[0035] In a preferred embodiment, examples of a heteroaryl group, asdefined for R₁, include 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl,4-pyridyl and pyrazinyl.

[0036] “Fused heterocyclic ring system” means an aromatic ornon-aromatic, 5-8 membered ring which is optionally fused with one ormore 5-6 membered rings. These fused 5-6 membered rings include aromaticgroups, such as phenyl, 1-napthyl, 2-naphthyl, indenyl, azulenyl,fluorenyl and anthracenyl, and non-aromatic rings such as cyclopentyl,cyclohexyl, piperidinyl, piperazinyl, pyrrolyl and tetrahydofuryl.Examples of fused ring systems include: benzo[1,3]dioxolyl,benzo[b]thiophenyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl,indolinyl, benzo[b]furanyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl,purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl.

[0037] In a preferred embodiment, compounds of the present inventionthat are useful in treating AIDS have the structure of Formula II, shownbelow.

[0038] In Formula II, R¹, R², R³, R⁴, R⁵, R⁶ and Z are as defined forFormula I while B² is as defined in Formula Ia.

[0039] In yet another embodiment of the present inventions, compoundshaving the structure of Formula III, as follows, are preferred chemicalintermediates from which compounds, or pharmaceutically acceptablesalts, solvates or prodrugs, useful for the treatment of AIDS areformed. Even more preferentially, the compounds of Formula III areuseful, themselves, as prodrugs and can be administered as a prodrug toa patient as a compound or in a pharmaceutical formulation.

[0040] In Formula III, R¹, R², R³, R^(4a), R⁵, R⁶ and Z are as definedfor Formula Ia.

[0041] In a more preferred embodiment, compounds of the presentinvention have the structure of Formula V, shown below.

[0042] wherein:

[0043] W¹ is a bond or a C₁-C₄ alkylene group;

[0044] R¹¹ is aryl, aryloxy, aryl-cyclopropylene, heteroaryl,heteroaryloxy, wherein R¹¹ is optionally substituted from 1-3 times withhalo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or wherein R¹¹ is H;

[0045] Y¹ is a bond, C₁-C₃ alkylene or —O—C₁-C₂ alkylene;

[0046] each R¹³ is independently selected from H, halo, N₂O, C₁-C₄alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, phenyl, phenoxy, benzyl,benzyloxy, p-halophenyl, p-halobenzyl, p-halophenoxy andp-halobenzyloxy; and

[0047] B² is as defined in for Formula Ia.

[0048] In an even more preferred embodiment, compounds of the presentinvention have the structure of Formula VI, shown below.

[0049] wherein:

[0050] W² is C₁-C₃ alkylene;

[0051] R¹¹ is aryl, aryloxy, aryl-cyclopropylene, heteroaryl,heteroaryloxy, wherein R¹¹ is optionally substituted from 1-3 times withhalo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹¹ is H;

[0052] Y² is a bond, C₁-C₃ alkylene;

[0053] each R¹⁴ is independently selected from H, halo, C₁-C₂ alkylC₁-C₂ alkoxy, C₁-C₂ haloalkyl;

[0054] and B² is as defined for Formula Ia.

[0055] In an alternate embodiment, compounds of the present inventionhave the structure of Formula VII, shown below.

[0056] wherein:

[0057] each Q is a bond or a methylene group;

[0058] each R¹⁵ is independently selected from H, halo, NO₂, C₁-C₄alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and CONHCH₃;

[0059] R¹⁶ is H or C₁-C₂ alkyl; and B² is as defined for Formula Ia.

[0060] By virtue of its acidic moiety, where applicable, a compound ofFormula I forms salts by the addition of a pharmaceutically acceptablebase. Such base addition salts include those derived from inorganicbases which include, for example, alkali metal salts (e.g. sodium andpotassium), alkaline earth metal salts (e.g. calcium and magnesium),aluminum salts and ammonium salts. In addition, suitable base additionsalts include salts of physiologically acceptable organic bases such astrimethylamine, triethylamine, morpholine, pyridine, piperidine,picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine,2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bishydroabietylamine, glucamine, N-methylglucamine, collidine,quinine, quinoline, ethylenediamine, ornithine, choline,N,N′-benzylphenethylamine, chloroprocaine, diethanolamine, diethylamine,piperazine, tris(hydroxymethyl)aminomethane and tetramethylammoniumhydroxide and basic amino acids such as lysine, arginine andN-methylglutamine. These salts may be prepared by methods known to thoseskilled in the art.

[0061] Salts of an amine group may also comprise quaternary ammoniumsalts in which the amino nitrogen carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety.

[0062] Compounds of Formula I, which are substituted with a basic group,may exist as salts formed through acid addition. The acid addition saltsare formed from a compound of Formula I and a pharmaceuticallyacceptable inorganic acid, including but not limited to hydrochloric,hydrobromic, hydroiodic, sulfuric, phosphoric, or organic acid such asp-toluenesulfonic, methanesulfonic, acetic, benzoic, citric, malonic,fumaric, maleic, oxalic, succinic, sulfamic, or tartaric. Thus, examplesof such pharmaceutically acceptable salts include chloride, bromide,iodide, sulfate, phosphate, methanesulfonate, citrate, acetate,malonate, fumarate, sulfamate, and tartrate.

[0063] Certain compounds of Formula I, and their salts, may also existin the form of solvates with water, for example hydrates, or withorganic solvents such as methanol, ethanol or acetonitrile to form,respectively, a methanolate, ethanolate or acetonitrilate. The presentinvention includes each solvate and mixtures thereof.

[0064] This invention also encompasses pharmaceutically acceptableprodrugs of the compounds of Formula I. Prodrugs are derivatives of thecompounds of the invention which have chemically or metabolicallycleavable groups and become, by solvolysis or under physiologicalconditions, the compounds of the invention which are pharmaceuticallyactive in vivo.

[0065] A prodrug of a compound of Formula Ia may be formed in aconventional manner with a functional group of the compounds such aswith an amino, hydroxy or carboxy group. The prodrug derivative formoften offers advantages of solubility, tissue compatibility, or delayedrelease in a mammalian organism (see, Bundgard, H., Design of Prodrugs,pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acidic compound witha suitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. Simple aliphatic or aromatic estersderived from acidic groups pendent on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy) alkyl esters or(alkoxycarbonyl)oxy)alkyl esters. Examples of prodrugs of compounds ofthe present invention include the compounds described in Examples143-146 as well as the ester chemical intermediates from which thecompounds of Examples 1-57 were formed.

[0066] In a preferred embodiment, the prodrugs of the present inventioncomprise compounds of Formula III, examples of which are furtherprovided in the exemplification.

[0067] In addition, a compound of Structural Formula I, or a salt,solvate or prodrug thereof, may exhibit polymorphism. The presentinvention also encompasses any such polymorphic form.

[0068] Certain compounds of Structural Formula I may contain one or morechiral centers and exist in different optically active forms. Whencompounds of Structural Formula I contain one chiral center, thecompounds exist in two enantiomeric forms. The present inventionincludes both enantiomers and mixtures of enantiomers such as racemicmixtures. The enantiomers may be resolved by methods known to thoseskilled in the art, for example, by formation of diastereoisomeric saltswhich may be separated by crystallization, gas-liquid or liquidchromatography, selective reaction of one enantiomer with anenantiomer-specific reagent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by aseparation technique, then an additional step is required to form thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

[0069] Certain compounds of Structural Formula I may also exist indifferent stable conformational forms which may be separable. Torsionalasymmetry due to restricted rotation about an asymmetric single bond,for example because of steric hindrance or ring strain, may permitseparation of different conformers. The present invention includes eachconformational isomer of compounds of Structural Formula I and mixturesthereof.

[0070] Certain compounds of Structural Formula I may exist inzwitterionic form and the present invention includes each zwitterionicform of compounds of Structural Formula I and mixtures thereof.

[0071] The compounds of this invention can also exist as tautomers;therefore the present invention also includes all tautomeric forms.

[0072] The compounds of Formula Ia are useful in the inhibition of HIVintegrase, the prevention or treatment of infection by the humanimmunodeficiency virus and the treatment of consequent pathologicalconditions such as AIDS or ARC. The treatment involves administering toa patient, in need of such treatment, a compound of Formula Ia, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, solvate or prodrug therefor.

[0073] It will be appreciated by those skilled in the art that referenceherein to treatment extends to prophylaxis as well as the treatment ofestablished infections or symptoms. This includes initiating treatmentpre- and post-exposure to the virus. In addition, the present inventioncan be administered in conjunction with other anti-HIV agents,immunomodulators, antiinfectives and/or vaccines.

[0074] The compounds of the present invention are also useful in thepreparation and execution of screening assays for antiviral compounds.Further, the compounds of the present invention are useful inestablishing or determining the binding site of other antiviralcompounds to HIV integrase, for example, by competitive inhibition.

[0075] The compounds of the present invention may be administeredorally, parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles.

[0076] This invention also provides a pharmaceutical composition for usein the above-described therapeutic method. A pharmaceutical compositionof the present invention comprises an effective amount of a compound ofFormula I in association with a pharmaceutically acceptable carrier,excipient or diluent.

[0077] The active ingredient in such formulations comprises from 0.1percent to 99.9 percent by weight of the formulation. By“pharmaceutically acceptable’ it is meant that the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

[0078] The present pharmaceutical compositions are prepared by knownprocedures using well-known and readily available ingredients. Thecompositions of this invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, beadlets,lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols, (as a solid or in a liquid medium), soft and hard gelatincapsules, suppositories, sterile injectable solutions, sterile packagedpowders and the like.

[0079] The compounds can be administered by a variety of routesincluding oral, intranasally, rectal, transdermal, subcutaneous,intravenous, intramuscular and intranasal.

[0080] When administered orally, these compositions are preparedaccording to techniques well-known in the art of pharmaceuticalformulation. For oral administration, the compound is typicallyformulated with excipients such as binders, fillers, lubricants,extenders, diluents, disintegration agents and the like as are known inthe art.

[0081] For parenteral administration, the compound is formulated inpharmaceutically acceptable non-toxic, parenterally-acceptable diluentsor solvents, such as mannitol, 1,3-butanediol, water, 5 percentdextrose, Ringer's solution or isotonic sodium chloride solution, orsuitable dispersing or wetting and suspending agents, such as sterile,bland, fixed oils, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0082] A compound of the present invention, or a salt or solvatethereof, can be formulated in unit dosage formulations comprising a dosebetween about 0.1 mg and about 1000 mg, or more, according to theparticular treatment involved. An example of a unit dosage formulationcomprises 5 mg of a compound of the present invention in a 10 mL sterileglass ampoule. Another example of a unit dosage formulation comprisesabout 10 mg of a compound of the present invention as a pharmaceuticallyacceptable salt in 20 mL of isotonic saline contained in a sterileampoule.

[0083] The compounds of the present invention can also be administeredto humans in a dosage range of 1 to 100 mg/kg body weight in divideddoses. One preferred dosage range is 1 to 20 mg/kg body weight orally individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the route of administration, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the host undergoing therapy.

[0084] General methods useful for the synthesis of compounds embodied inthis invention are shown below. The preparations shown below aredisclosed for the purpose of illustration and are not meant to beinterpreted as limiting the processes to make the compounds by any othermethods.

[0085] It will be appreciated by those skilled in the art that a numberof methods are available for the preparation of the compounds of thepresent invention as provided by Structural Formula I. A compound ofStructural Formula I may be prepared by processes which includeprocesses known in the chemical art for the production of structurallyanalogous compounds or by a novel process described herein. A processfor the preparation of a compound of Structural Formula I (or apharmaceutically acceptable salt thereof) and novel intermediates forthe manufacture of a compound of Formula I, as defined above, providefurther features of the invention and are illustrated by the followingprocedures in which the meanings of the generic radicals are as definedabove, unless otherwise specified. It will be recognized that it may bepreferred or necessary to prepare a compound of Formula I in which afunctional group is protected using a conventional protecting group thento remove the protecting group to provide the compound of Formula I.

[0086] Thus, there is provided a process for preparing a compound ofFormula I (or a pharmaceutically acceptable salt thereof) as provided inany of the above descriptions which is selected from any of thosedescribed in the examples, including the following. As shown below inScheme I, in one method an appropriately substituted methyl-carbonyl,such as a methyl ketone, acetylamide or acetylhydrazide, is condensedwith oxalic acid ester under basic conditions to form a diketobutyricacid of the present invention. A representative procedure has beendescribed by Gramain (Gramian, J. -F.; Remuson, R., Vallee D. J. Org.Chem. 1985, 50, 710). A variety of bases can be used to effect thisreaction including LDA, LiHMDS, tBuOK, NaOMe, NaOEt, NaH or MeOCO₂MgOMe.In addition there a number of oxalic acid derivatives that have beendisclosed which may be useful in the formation of the diketobutyric acidgroup (de las Heras, M. A.; Vaquerao, J. J.; García-Navio, J. L.;Alvarez-Builla, J. J. Org. Chem. 1996, 61, 9009). This method isgenerally applicable to the compounds embodied by Formula I.

[0087] Exemplification

[0088] The specific examples that follow illustrate the syntheses of thecompounds of the instant invention, and are not to be construed aslimiting the invention in sphere or scope. The methods may be adapted tovariations in order to produce compounds embraced by this invention butnot specifically disclosed. Further, variations of the methods toproduce the same compounds in somewhat different manner will also beevident to one skilled in the art.

[0089] In the following experimental procedures, all temperatures areunderstood to be in Centigrade (C) when not specified. The nuclearmagnetic resonance (NMR) spectral characteristics refer to chemicalshifts (d) expressed in parts per million (ppm) versus tetramethylsilane(TMS) as reference standard. The relative area reported for the variousshifts in the proton NMR spectral data corresponds to the number ofhydrogen atoms of a particular functional type in the molecule. Thenature of the shifts as to multiplicity is reported as broad singlet (bsor br s), broad doublet (bd or br d), broad triplet (bt or br t), broadquartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet(q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), anddoublet of quartet (dq). Examples of solvents employed for taking NMRspectra are acetone-d₆ (deuterated acetone), DMSO-d₆(perdeuterodimethylsulfoxide), D₂O (deuterated water), CDCl₃(deuterochloroform) and other conventional deuterated solvents such asdeuterated methanol.

[0090] The abbreviations used herein are conventional abbreviationswidely employed in the art. Some of which are: calcd (calculated); DMSO(dimethylsulfoxide); EtOAc (ethyl acetate); HPLC (high-pressure liquidchromatography); LC/MS (liquid chromatography, mass spectroscopy); LDA(lithium diisopropyl amide); LiHMDS (lithium bis (trimethylsilyl)amide);SiO₂ (silica gel); THF (tetrahydrofuran), Me (methyl), Et (ethyl), Ph(phenyl), tBuOK (potassium tert-butoxide), NaOMe (sodium methoxide), andNaOEt (sodium ethoxide).

[0091] Many compounds were analysed using the following LC/MSconditions:

[0092] Column: Luna 5μ C-8, 4.6×30 mm

[0093] Solvents: Solvent A: 10% CH₃CN-90% H₂O, 5 mM NH₄OAc

[0094] Solvent B: 90% CH₃CN-10% H₂O, 5 mM NH₄OAc

[0095] Gradient: 100% solvent A/0% solvent B to 0%

[0096] solvent A/100% solvent B

[0097] Gradient time: 2 minutes, hold time 1 minute.

[0098] Flow rate: 4 ml/min.

[0099] Detector wavelength: 220 nm.

[0100] Spectrometry (MS) data were determined with a Micromass ZMDPlatform for LC in electrospray mode.

[0101] The compounds and chemical intermediates of the presentinvention, described in the following examples, were prepared accordingto the following methods.

[0102] Aryl halide (4.6 mmol) was dissolved in 1 mL of THF and 23 mL of2M MeNH₂ in THF added. The resulting mixture was allowed to stirovernight resulting in a suspension. This was filtered and the solventremoved under vacuum to yield crude amine, which was taken on to thenext step without further purification. This method can also be utilizedwith compounds similar to the aryl halide starting material.

[0103] Step 1:

[0104] Substituted benzoic acid (50 mmol) and1-hydroxybenzotriazolehydrate (50 mmol) were combined in a round bottomflask and dissolved in 25 mL of DMF. To this solution was added amine(50 mmol) in THF and triethylamine (150 mmol) followed by HBTU[O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate] (75 mmol). The reaction was allowed to proceedovernight after which, H₂O was added and the resulting solutionextracted with ethyl acetate. The organic layer was separated, washedwith H₂O, dried over Na₂SO₄, filtered and solvent removed. The crudeproduct was isolated by flash column chromatography (SiO₂, Hexanes/ethylacetate).

[0105] Alternatively, to a solution of amine (139 mmol), 140 mL of 1NNaOH and 130 mL of methylene chloride was added substituted benzoylchloride (139 mmol). The resulting mixture was stirred 1 h, after whichtime the organic layer was separated, washed with H₂O and dried overNa₂SO₄. After filtration the solvent was removed and the product carriedon to the next step without further purification. This method can alsobe utilized with compounds similar to the substituted benzoic acidstarting material.

[0106] Step 2:

[0107] The resultant amide (123 mmol) was dissolved in 180 mL of THF.5.51 mL of BF₃.Et₂O was added and the resulting solution heated toreflux for 15 min. The reaction was then cooled to −20-40° C. andBH₃.DMS added with a dropping funnel over 10 min. The reaction vesselwas then fitted with a distillation condenser, then heated to reflux andsolvent removed over 20 min. The distillation condenser was replacedwith reflux condenser and the solution heated to 110° C. for 2 h. Aftercooling to room temp 75 mL of 6N HCl was added and then the resultingmixture heated to reflux for 1 h. The solution was then allowed to coolto room temp and 200 mL of 6 N NaOH was slowly added. The resultingmixture was extracted with Et₂O and the organic layer was washed withsatd NaCl (aq.), dried over Na₂SO₄, filtered and the solvent removedunder vacuum. The resulting oil was dissolved in Et₂O and 30 mL of 4NHCl (dioxane) added to form a precipitate.

[0108] Alternatively, a solution of the amide (13.2 mmol) intetrahydrofuran (75 ml) was treated with lithium aluminum hydride (1.0g, 26.3 mmol) and the resulting mixture was heated under reflux for 1 h.The cooled mixture was hydrolyzed by the successive addition of water (1ml), 15% sodium hydroxide solution (1 ml) and water (3 ml). The solidformed was filtered and the filtrate was concentrated under reducepressure. Chromatography of the residue on silica gel (elutiondichloromethane/methanol) gave the pure product.

[0109] Aryl aldehyde (2.6 mmol) and 3.9 mL of 2 M methyl amine in THFwere dissolved in 0.5 mL of EtOH followed by the addition of NaBH₄ (13mmol). The resulting mixture was stirred overnight, after which it wasfiltered and the filtrate acidified with 10% H₂SO₄ (aq.). This waswashed with Et₂O then neutralized with 10 N NaOH. The resulting mixturewas extracted with Et₂O, the organic layer separated and washed withsatd NaCl, dried over Na₂SO₄, filtered and the solvent removed undervacuum to yield pure amine. This method can also be utilized withcompounds similar to the aryl aldehyde starting material.

[0110] To a solution of amine (7.3 mmol) in a 1:1 mixture of 50 mL ofCH₂Cl₂ and Satd NaHCO₃ (aq.) was added AcCl (14.7 mmol). The resultingmixture was stirred overnight after which the organic layer wasseparated, dried over Na₂SO₄, filtered and solvent removed to yield pureproduct. This method can also be utilized with amine compounds similarto the above-identified starting material.

[0111] Step 1:

[0112] Benzyl halide (6.67 mmol) was dissolved in 5 ml of THF. To thiswas added 5 ml of 40% (aq.) methylamine and the resulting mixturestirred 15 min. The reaction mixture was transferred to a separatoryfunnel, diluted with 100 ml H₂O and extracted with 100 ml of ethylacetate. The organic solution was washed with brine, dried over Na₂SO₄then filtered and the solvent removed. The crude product was purified bycolumn chromatography (SiO₂, 2-10% EtOH/CH₂Cl₂). This method can also beutilized with compounds similar to the benzyl halide starting material.

[0113] Step 2:

[0114] The intermediate amine (4.6 mmol) synthesized above was dissolvedin 30 ml CH₂Cl₂. Satd. (aq.) NaHCO₃ was added followed by CH3COCl (5.0mmol) and the resulting mixture stirred for 1 h. The organic layer wasseparated, washed with brine dried over Na₂SO₄ then filtered and thesolvent removed to yield pure product.

[0115] Step 1:

[0116] Benzyl halide (11.1 mmol) was dissolved in 11 mL of THF, to whichwas added R₃NH₂ (22.1 mmol). The resulting reaction was stirred for 2hduring which a white precipitate forms. The solid was filtered andwashed with THF. Solvent was removed from the THF solution under vacuum.This method can also be utilized with compounds similar to the benzylhalide starting material.

[0117] Step 2:

[0118] The product of step 1 was dissolved in 75 mL of methylenechloride, to which 75 mL of satd NaCO₃ (aq.) was added followed byacetyl chloride (22.1 mmol). The mixture was stirred for 2 hours. Theorganic layer was separated, washed with satd NaCl, dried over Na₂SO₄,filtered and the solvent removed under vacuum to yield crude product.The product was purified by flash column chromatography (SiO₂,EtOAc/Hexanes).

[0119] Sodium hydride (60% in mineral oil) (27.5 mmol) was measured intoa round bottom flask and triturated with hexanes. To this was addedN-alkylacetamide (13.8 mmol) dissolved in 34 mL of toluene. To theresulting suspension was added benzyl halide (6.9 mmol) and the reactionmixture stirred overnight. The mixture was then filtered and the solventremoved under vacuum. The product was purified by flash columnchromatography (SiO₂, EtOH/methylene chloride). This method can also beutilized with compounds similar to the N-alkylacetamide startingmaterial.

[0120] Method VIII:

[0121] A solution of amine (7.63 mmol), as in Method IV, in a mixture ofpyridine (10 ml) and acetic anhydride was stirred at 22° C. for 2 h. Theexcess reagents were evaporated in vacuo and the residue was filtered ona silica gel pad (elution toluene—ethyl acetate) to give pure product.

[0122] Acetyl amide (9.92 mmol) was dissolved in 20 ml of anhydrous THFunder an N₂ atmosphere then cooled to −78° C. To this was added 30 ml of1M LiHMDS (lithium bis(trimethylsilyl)amide) and the reaction mixturestirred for 20 min. at which point dimethyl oxalate (14.9 mmol)dissolved in 8 ml of THF was added. The reaction was allowed to continueat −78° C. for 20 min. then warmed to 0° C. and stirred an additional 45min. 1 N HCl was added and the resulting mixture extracted with EtOAc.The organic solution was washed with brine, dried over Na₂SO₄ thenfiltered and the solvent removed. The crude product was purified byreverse phase preparative HPLC (C₁₈, MeOH/H₂O (0.1% TFA)-gradient),flash column chromatography (SiO₂, Hexanes/EtOAc) or carried onto thenext step without further purification.

[0123] Alternatively, acetyl amide (54 mmol) and dimethyl oxalate (81mmol) were dissolved in 54 mL of THF and cooled to 0° C. To thissolution was added 108 mL of 1N LiHMDS (THF) dropwise via an additionfunnel. The resulting mixture was stirred at 0° C. for 1 h, after whichthe reaction was quenched with 1N HCl. The solution was extracted withmethylene chloride, the organic layer separated, dried over Na₂SO₄,filtered and the solvent removed under vacuum to yield crude product.The compound was purified by flash chromatography (SiO₂, Hexanes/ethylacetate).

[0124] This method can also be utilized with compounds similar to theacetyl amide starting material.

[0125] To a solution of methyl ester (0.33 mmol) dissolved in 0.4 ml ofMeOH was added 0.4 ml of 1N NaOH. After stirring for 1 h, 0.4 ml of 1NHCL was added and the resulting mixture extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄ then filtered andthe solvent removed under vacuum. The crude product was purified byreverse phase preparative HPLC (C₁₈, MeOH/H₂O (0.1%TFA)). This methodcan also be utilized with compounds similar to the above-identifiedstarting material.

[0126] The methyl ester (5.5 mmol) was suspended in 16.5 mL of 1N NaOH(aq.) with rapid stirring. To this was added THF, dropwise until all thesolid had dissolved. After stirring the resulting solution an additional20 min., it was transferred to a separatory funnel, washed with CH₂Cl₂,acidified with 1 N HCl and the product extracted with EtOAc. The organiclayer was dried over Na₂SO₄, filtered and the solvent removed to yieldcrude product. The crude product could be purified by preparative HPLC(C₁₈, MeOH/H₂O, 0.1% TFA). This method can also be utilized with methylester compounds similar to the above-identified starting material.

[0127] Acetyl amide (2.0 mmol) was dissolved in 10 mL of THF and theresulting solution cooled to −78° C., after which 4.0 mL of 1N LiHMDS(in THF) was added. The resulting solution was allowed to stir for 20min. Dimethyloxalate (0.36 grams, 3.0 mmol), dissolved in 2 mL of THFwas then added and the reaction stirred for 3 h at −78° C. The reactionwas warmed to 0° C. and stirred an additional 20 min. before beingquenched with 1 N HCl. The mixture was extracted with EtOAc, and theorganic layer dried over MgSO₄. The solution was filtered and solventremoved to yield the crude methyl ester. The crude ester was eithertaken on to the next step crude or purified by preparative HPLC (C₁₈,MeOH/H₂O-0.1% TFA).

[0128] The intermediate methyl ester was dissolved in a 1:1 mixture of1N NaOH and THF and stirred for 2 h. THF was then removed under vacuumand the solution acidified with 1 N HCl. Solvent was then removed undervacuum to yield crude product, which was purified by preparative HPLC(C₁₈, MeOH/H₂O-0.1%TFA).

[0129] This method can also be utilized with compounds similar to theacetyl amide starting material.

[0130] Method XIII:

[0131] Preparation of(Z)-2,2-Dimethyl-5-(carboxymethylene)-1,3-dioxolane-4-one (IV)

[0132] Step 1: Preparation of(S)-(+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid,Tert-butyldiphenylsilyl Ester (I):

[0133] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid (2.08 g, 11.9 mmol), which was derived from L-malic acid by meansknown in the art, in dry dichloromethane (20 ml) was treated withtriethylamine (1.83 ml, 13.1 mmol) followed by a solution oft-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reactionmixture was diluted with toluene (250 ml) washed with water, saturatedsodium bicarbonate, brine and dried over magnesium sulfate. Evaporationof the solvent under reduced pressure and chromatography of the residueon silica gel (4×12 cm) using a mixture of toluene and ethyl acetate(0-2%) as eluent gave 4.90 g (99%) of the title material as a clear oil.¹H NMR (400 MHz, CDCl₃) δ: 1.13 (s, 9), 1.58 (s, 3), 3.05 (m, 2), 4.79(dd, 1, J=4, 7), 7.4-7.8 (m, 10).

[0134] Step 2: Preparation of4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid,Tert-butlydiphenylsilyl Ester (II):

[0135] A solution of (S)-(+)-2,2-dimethyl-5-oxo -1,3-dioxolane -4-aceticacid, tert-butyldiphenylsilyl ester (21.65 g, 52.4 mmol) in carbontetrachloride (160 ml) was treated with N-bromosuccinimide (9.35 g, 52.4mmol) and 2,2′-azobisisobutyronitrile (200 mg) and the resulting mixturewas heated under reflux (bath temperature 85° C.) while irradiating witha 500 watt lamp. After 10 minutes, the reaction mixture was cooled andthe succinimide was filtered. The solvent was evaporated under vacuum togive the title bromide as a light yellow oil (˜26 g) which was usedimmediately for the next step. ¹H NMR (400 MHz, CDCl₃) δ: 1.12 (s, 9),1.41 (s, 3), 1.80 (s, 3), 3.80 (m, 2), 7.3-7.7 (m, 10).

[0136] Step 3: Preparation of(Z)-2,2-Dimethyl-5-(tert-butyldiphenylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (III):

[0137] A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane -4-aceticacid, tert-butyldiphenylsilyl ester (˜26 g, 52.4 mmol) in drytetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5minutes with 1,8-diazabicyclo [5,4,0] undec-7-ene (12.7 g, 78.8 mmol)and the resulting mixture was stirred at 5° C. for 1.5 hour. The solidformed was filtered and washed with a small amount of tetrahydrofuran.The filtrate was used as such for the next step.

[0138] Alternatively, the reaction mixture can be diluted with toluene,washed with water, saturated sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent gave an oil which waschromatographed on silica gel using a mixture of toluene and ethylacetate (0-2%) as eluent. The title ester was obtained as an oil in30-50% yield. ¹NMR (400 MHz, CDCl₃) δ: 1.16 (s, 9), 1.76 (s, 6), 5.97(s, 1), 7.4-7.8 (m, 10)

[0139] Step 4: Preparation of(Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (IV) from Pure(III):

[0140] A solution of pure (Z)-2,2dimethyl-5-(t-butyldiphenylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (2.80 g, 6.82 mmol) in tetrahydrofuran (40 ml) wastreated at 22° C. with acetic acid (2 ml) followed by 6.8 ml of a 1 Msolution of tetrabutylammonium fluoride in tetrahydrofuran. After 15minutes at 22° C., the reaction mixture was diluted with ethyl acetate,washed with water, brine and dried (magnesium sulfate). The solvent wasconcentrated under reduced pressure and the residue was triturated withtoluene to give 1.00 g (85%) of the title compound as a whitecrystalline material: mp 203-204° C. (dec.). IR (KBr) ν max (cm⁻¹):1805, 1707 and 1662. ¹H NMR (400 MHz, CDCl₃) δ: 1.78 (s, 6), 5.89 (s,1). Anal. calcd for C₇H₈O₅: C, 48.84; H, 4.68; found: C, 48.84; H, 4.65.

[0141] Preparation of (Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (IV) from Crude (III):

[0142] A solution of the crude(Z)-2,2-dimethyl-5-(tert-butyldiphenylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (52.4 mmol) in tetrahydrofuran (200 ml)was treated with acetic acid (13 ml) followed with 50 ml of a 1 Msolution of tetrabutylammonium fluoride in tetrahydrofuran. After 15minutes at 22° C., the reaction mixture was filtered and the filtratewas concentrated in vacuo. Trituration of the residue with toluene gave6.3 g (70% for three steps) of the title material as a white solid (>95%pure by ¹HNMR).

[0143] A solution of (Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (0.214 g, 1.24 mmol) and amine(1.24 mmol) in acetonitrile (15 ml) was treated at 22° C. withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) (0.550 g, 1.24 mmol) followed by triethylamine (0.18 ml, 1.29mmol). After 2 hours, the reaction mixture was diluted with ethylacetate, washed with water, saturated sodium bicarbonate, brine anddried (magnesium sulfate). Evaporation of the solvent and chromatographyof the residue on silica gel (elution toluene-ethyl acetate) gave amideas an oil or solid. This method can also be utilized with aminecompounds similar to the above-identified starting material.

[0144] The amine (0.1 mmol) was treated with 0.5 ml of a 0.3M stocksolution of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP®) (1.5 eq) and triethylamine (1.5 equivalent)in dichloromethane followed by 0.5 ml of a 0.2 M solution of(Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (1 eq) in amixture of dichloromethane-N,N-dimethylformamide (10:1). After 16 h at22° C., the mixtures were purified using a Shimadzu automatedpreparative HPLC system (Primesphere C-8, 5 , 21×100 mm, H₂O 5 mMNH₄OAc—acetonitrile). This method can also be utilized with compoundssimilar to the amine starting material.

[0145] Method XVI:

[0146] Preparation of(Z)-2,2-Dimethyl-5-(carboxymethylene)-1,3-dioxolane-4-one (IV)

[0147] Step 1: Preparation of(+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid,Tert-butyldimethylsilyl Ester (V):

[0148] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid (13.20 g, 75.8 mmol), which was derived from L-malic acid by meansknown in the art, in N,N-dimethylformamide (25 ml) was treated at 22° C.with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilylchloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at22° C. for 18 h. The reaction mixture was then diluted with toluene (500ml), washed with water (×3), saturated sodium bicarbonate and brine.After drying (magnesium sulfate), the solvent was evaporated underreduced pressure to give an oil. Distillation under vacuum gave 20.9 g(96%) of the title material as a clear oil Bp 80-90° C./0.1 torr (bulbto bulb distillation, air bath temperature). ¹H NMR (400 MHz, CDCl₃) δ:0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72(m, 2), 4.35 (dd, 1, J=4, 6).

[0149] Step 2: Preparation of4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid,Tertbutyldimethylsilyl Ester (VI):

[0150] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid, t-butyldimethylsilyl ester (20.9 g, 72.4 mmol) in carbontetrachloride (200 ml) was treated with N-bromosuccinimide (14.18 g,79.6 mmol) and 2,2′-azobisisobutyronitrile (0.30 g) and the resultingmixture was heated under reflux while irradiating with a 500 W lamp.After ˜5 min., a mild exothermic reaction was observed and the mixturewas heated for an additional 5 min. The reaction mixture was then cooledin an ice bath and the floating succinimide was filtered and washed witha small amount of carbon tetrachloride. The filtrate was usedimmediately as such for the next step. ¹H NMR (400 MHz, CDCl₃) δ: 0.27(s, 3), 0.28 (s, 3), 0.94 (s, 9), 1.66 (s, 3), 1.84 (s, 3), 3.62 (m, 2).

[0151] Step 3: Preparation of(Z)-2,2-Dimethyl-5-(tert-butyldimethylsilyloxycarbonyl-methylene)-1,3-dioxolane-4-one (VII):

[0152] The solution of crude4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid,tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (˜220ml) was cooled to 0-5° C. and treated dropwise over 10 min. and undergood stirring with a solution of 1,8-diazabcyclo 5,4,0 undec-7-ene (12.1g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitate wasformed which gradually became a granular solid. After 1 h, the solidobtained was filtered and washed with a small amount of tetrahydrofuran.The filtrate was concentrated under reduced pressure to give a lightorange oil which was used as such for the next step.

[0153] Step 4: Preparation of(Z)-2,2-Dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (V):

[0154] The crude (Z)-2,2-dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one(72.4 mmol) in tetrahydrofuran (50 ml) was treated at 22° C. with aceticacid (13 ml, 0.227 mmol) followed by 73 ml (73.0 mmol) of a 1M solutionof tetrabutylammonium fluoride in tetrahydrofuran. After 1 h at 22° C.,the reaction mixture was diluted with ethyl acetate (500 ml), washedwith water, brine and dried (anhydrous magnesium sulfate). Evaporationof the solvent under reduced pressure and trituration of the residualsolid with toluene (50 ml) gave 7.70 g (62% for 3 steps) of the titleZ-isomer as a white crystalline solid. Concentration of the motherliquors yielded another 0.2 g of a 75:25 mixture of Z and E isomers.Z-Isomer; ¹H NMR (400 MHz, CDCl₃) δ: 1.78 (s, 3), 5.89 (s, 1). E-Isomer:¹H NMR (400 MHz, CDCl₃) δ: 1.80 (s, 3), 6.03 (s, 1).

[0155] Preparation of(Z)-2,2-Dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one (VIII):

[0156] A mixture of(Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (0.50 g, 2.9mmol) in dry dichloromethane (10 ml) was treated at 22 ° C. with oxalylchloride (0.5 ml, 5.8 mmol) followed by a trace (capillary) ofN,N-dimethylformamide. After 1 h at 22° C., the clear solution wasconcentrated in vacuo to give 0.55 g (quantitative) of the title acidchloride as a white crystalline solid.

[0157] (Z)-2,2-Dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolane (1.3mmol) was dissolved in 5 mL of THF. To this was added an amine (1.5mmol) followed by Et₃N (2.6 mmol). The resulting slurry was stirred for2 h then filtered. The mother liquor was isolate, and the solventremoved under vacuum to yield crude product which was purified by flashcolumn chromatography (SiO₂, CH₂Cl₂/EtOH). This method can also beutilized with amine compounds similar to the above-identified startingmaterial.

[0158] A solution of dioxolane (0.62 mmol) in tetrahydrofuran (5 ml) wastreated with 1 ml of 1 M aqueous sodium hydroxide and the resultingclear solution was stirred at 22° C. for 30 minutes. The reactionmixture was then acidified with 2 N hydrochloric acid and diluted withethyl acetate. The organic phase was washed with brine, dried (magnesiumsulfate) and evaporated under reduced pressure. This method can also beutilized with dioxolane compounds similar to the above-identifiedstarting material.

[0159] Dioxolane (˜0.05 mmol) in a mixture of tetrahydrofuran (0.5 ml)and water (0.3 ml) was treated at 22° C. with 0.15 ml of 1 M aqueoussodium hydroxide and the resulting mixture was stirred for 1.5 h. Thereaction mixture was then quenched by the addition of 0.3 ml of 1Mtrifluoroacetic acid in acetonitrile and filtered on a Varian Bond EluteC-18 cartridge (1.5 g) using water and then water—acetonitrile (1:1) aseluent.

[0160] If not commercially available, a necessary starting material forthe preparation of a compound of Formula I may be prepared by aprocedure which is selected from standard techniques of organicchemistry including aromatic and heteroaromatic substitution andtransformation, from techniques which are analogous to the syntheses ofknown, structurally similar compounds, and techniques which areanalogous to the above described procedures or procedures described inthe Examples. It will be clear to one skilled in the art that a varietyof sequences is available for the preparation of the starting materials.Starting materials which are novel provide another aspect of theinvention. This method can also be utilized with dioxolane compoundssimilar to the above-identified starting material.

[0161] To a solution of dioxobutyric acid (0.58 mmol),1-hydroxybenzotriazole hydrate (BtOH.H₂O) (0.58 mmol), amine (0.75 mmol)and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) (0.88 mmol) in 4 mL of DMF was added Et₃N(1.72 mmol). The resulting mixture was stirred overnight, then dilutedwith EtOAc, washed H₂O and dried over MgSO₄. After filtration thesolvent was removed under vacuum to yield crude product which waspurified by preparative HPLC (C₁₈, MeOH/H₂O-0.1% TFA). This method canalso be utilized with compounds similar to the dioxobutyric acidstarting material.

EXAMPLE 1

[0162] Intermediate 1A: Methyl 4-(4-fluorobenzyloxy)-benzoate

[0163] A mixture of methyl p-hydroxybenzoate (4.38 g, 28.8 mmol),p-fluorobenzyl chloride (5.0 g, 34.6 mmol) and anhydrous potassiumcarbonate (10 g) in acetone (250 ml) was heated under reflux for 24 h.The solid was then filtered and the filtrate was evaporated underreduced pressure. Crystallization of the residue from hexane gave 7.20 g(96%) of the title ester as white plates: mp 93-94° C. ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.9 (3H, s, OCH₃), 5.1 (2H, s, CH₂), 7.0 (2H, d, J=8.8Hz, aromatics), 7.11 (2H, m, aromatics), 7.43 (2H, m, aromatics), 8.02(2H, d, J=8.8 Hz, aromatics). Anal. Calcd for C₁₅H₁₃FO₃: C, 69.22; H,5.03. Found: C, 68.89; H, 4.69.

[0164] Intermediate 1B: 4-(4-Fluorobenzyloxy)-benzoic Acid

[0165] A mixture of Intermediate 1A (7.2 g, 27.6 mmol) in 80% aqueousethanol (100 ml) was treated with sodium hydroxide (3.5 g) and theresulting mixture was heated at 50° C. for 2 h. The solvent wasevaporated under reduced pressure and the residual solid was dilutedwith water and acidified with concentrated hydrochloric acid (20 ml).Filtration of the resulting solid and crystallization from ethyl acetategave 6.05 g (89%) of the title acid as white plates: mp 213-215° C.¹HNMR 400 MHz (CDCl₃) δ (ppm): 5.16 (2H, s, CH₂), 7.1 (2H, d, m 8.9 Hz,aromatics), 7.24 (2H, m, aromatics), 7.53 (2H, m, aromatics), 7.9 (2H,d, J=8.9 Hz, aromatics) and 12.7 (1H, s, OH) Anal. Calcd for C₁₄H₁₁FO₃:C 68.29, H 4.50. Found: C 68.30, H 4.41.

[0166] Intermediate 1C: 4-(4-Fluorobenzyloxy)-N-methyl-benzylamine

[0167] Intermediate 1C was prepared from Intermediate 1B using MethodII, step 2. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.47 (3H, s, NCH₃), 3.72 (2H,s, NCH₂), 5.03 (2H, s, OCH₂), 6.95 (2H, d, J=8.6 Hz, aromatics), 7.09(2H, m, aromatics), 7.27 (2H, d, J=8.6 Hz, aromatics) 7.42 (2H, m,aromatics). HRMS (ESI⁺) calculated for C₁₅H₁₇FNO [M+H]: 246.1294: found:246.1285.

[0168] Intermediate 1D:N-{4-(4-Fluorobenzyloxy)-benzyl}-N-methylacetamide

[0169] Intermediate 1D was prepared from Intermediate 1C using MethodVIII. Solid: mp 82-83° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃)δ (ppm): mixture of rotamers; 2.16 and 2.19 (3H, 2 s, COCH₃), 2.93 and2.94 (3H, 2 s, NCH₃), 4.48 and 4.54 (2H, 2 s, NCH₂), 5.03 and 5.04 (2H,2 s, OCH₂), 6.95-7.44 (8H, m, aromatics). Anal. Calcd for C₁₇H₁₈FNO₂: C71.06, H 6.31, N 4.87. Found: C 70.99, H 6.23, N 4.74.

[0170] Intermediate 1E:3-{[4-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0171] Intermediate 1E was prepared from Intermediate 1D using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.01 (3H, s,NCH₃), 3.89 and 3.92 (3H, 2 s, OCH₃), 4.54 and 4.60 (2H, 2 s, NCH₂),5.03 (2H, s, OCH₂), 6.31 and 6.38 (1H, 2 s, CH), 6.94-7.44 (8H, m,aromatics). HRMS (MAB N₂) calculated for C₂₀H₂₀FNO₅ [M⁺]: 373.1314 :found: 373.1320.

[0172] Compound 1:3-{[4-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0173] Compound 1 was prepared from Intermediate 1E using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.93 and 2.94 (3H, 2s, NCH₃), 4.45 and 4.52 (2H, 2 s, NCH₂), 4.94 (2H, s, OCH₂), 6.27 and6.35 (1H, 2 s, CH), 6.85-7.35 (8H, m, aromatics). HRMS (MAB N₂ )calculated for C₁₉H₁₈FNO₅ [M⁺]: 359.1157 : found: 359.1167, δ 0.5 ppm.

EXAMPLE 2

[0174] Intermediate 2A:3-{1-Hydroxy-1-(4-fluorophenyl)-methyl}-N-methyl-benzamide

[0175] A solution of 3-bromo-N-methylbenzamide (3.48 g, 16.25 mmol) indry tetrahydrofuran (100 ml) was cooled to −78° C. and treated dropwiseover 10 min. with 13 ml (32.5 mmol) of a 2.5 M solution ofn-butyllithium in hexane. After 15 min. at −78° C., a solution of4-fluorobenzaldehyde (2.5 g, 20.1 mmol) in tetrahydrofuran (10 ml) wasadded dropwise over 10 min. and the resulting mixture was stirred foranother 45 min at the same temperature. The temperature was then allowedto reach −20° C. and the mixture was quenched by the addition ofsaturated ammonium chloride. The reaction mixture was then extractedwith ethyl acetate and the organic layer was washed with 0.1Nhydrochloric acid, saturated sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent and crystallization ofthe residue from ethyl acetate gave 1.60 g (38%) of the title compoundas a white solid : mp : 138-139° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.0and 3.01 (3H, 2 s, NCH₃), 5.88 (1H, s, CH), 6.19 (1H, broad, NH), 7.03(2H, m, aromatics), 7.36 (2H, m, aromatics), 7.41 (1H, t, J=7.6 Hz,aromatic), 7.49 (1H, d, J=7.6 Hz, aromatic), 7.66 (1H, d, J=7.6 Hz,aromatic), 7.79 (1H, s, aromatic). Anal. Calcd for C₁₅H₁₄FNO₂: C 69.49,H 5.44, N 5.40. Found: C 69.41, H 5.41, N 5.63.

[0176] Intermediate 2B: 3-(4-Fluorobenzyl)-N-methyl-benzamide

[0177] A solution of Intermediate 2A (1.0 g, 3.85 mmol) in ethyl acetate(150 ml) and acetic acid (1 ml) was hydrogenated over 0.5 g of 10%palladium on activated carbon and under 45 psi of hydrogen for 24 h.After filtration the solvent was evaporated under reduce pressure.Crystallization of the residue from a mixture of ethyl acetate andhexane gave 0.778 g of the title amide as white needles: mp 93-94° C.¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.02 and 3.03 (3H, 2 s, NCH₃), 4.01 (2H,s, CH₂), 6.12 (1H, broad, NH), 7.0 (2H, m, aromatics), 7.14 (2H, m,aromatics), 7.32 (1H, d, J=7.6 Hz, aromatic), 7.37 (1H, t, J=7.6 Hz,aromatic), 7.59 (1H, d, J=7.6 Hz, aromatic), 7.62 (1H, s, aromatic).Anal. Calcd for C₁₅H₁₄FNO: C 74.06, H 5.80, N 5.76. Found: C 73.74, H5.87, N 5.74.

[0178] Intermediate 2C: 3-(4-Fluorobenzyl)-N-methyl-benzylamine

[0179] Intermediate 2C was prepared from Intermediate 2B using MethodII, step 2. ¹HNMR 400 MHz (C₆D₆) δ (ppm) : 2.3 (3H, s, NCH₃), 3.59 (2H,s, CH₂), 3.76 (2H, s, CH₂), 6.85-7.25 (8H, m, aromatics). MS (ESI ⁺)(m/z): 230 (M+H ).

[0180] Intermediate 2D: N-{3-(4-Fluorobenzyl)-benzyl}-N-methylacetamide

[0181] Intermediate 2D was prepared from Intermediate 2C using MethodVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.16 and 2.17(3H, 2 s, COCH₃), 2.92 and 2.94 (3H, 2 s, NCH₃), 3.95 and 3.97 (2H, 2 s,CH₂), 4.51 and 4.57 (2H, s, NCH₂), 6.96-7.31 (8H, m, aromatics). MS(ESI⁺) (m/z): 272 (M+H). Anal. Calcd for C₁₇H₁₈FNO: C 75.25, H 6.69, N5.16. Found: C 74.99, H 6.75, N 5.08.

[0182] Intermediate 2E:3-{[3-(4-Fluoro-benzyl)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic AcidMethyl Ester

[0183] Intermediate 2E was prepared from Intermediate 2D using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.01 and 3.02(3H, 2 s, NCH₃), 3.88, 3.92 and 3.96 (5H, 3 s, CH₂ and OCH₃), 4.58 and4.64 (2H, 2 s, NCH₂), 6.32 (1H, s, CH), 6.97-7.54 (8H, m, aromatics).HRMS (MAB N₂) calculated for C₂₀H₂₀FNO₄ [M⁺]: 357.1376 : found:357.1375.

[0184] Compound 2:3-{[3-(4-Fluoro-benzyl)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0185] Compound 2 was prepared from Intermediate 2E using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 3.02 and 3.04 (3H, 2s, NCH₃), 3.76 (2H, s, CH₂), 4.56 and 4.64 (2H, 2 s, NCH₂), 6.37 (1H, s,CH), 6.96-7.33 (8H, m, aromatics ). HRMS (MAB N₂) calculated forC₁₉H₁₈FNO₄ [M⁺]: 343.12198: found: 343.12234, δ −1.0 ppm.

EXAMPLE 3

[0186] Intermediate 3A: Methyl 3-(4-fluorobenzyloxy)-benzoate

[0187] Reaction of methyl 3-hydroxybenzoate with p-fluorobenzyl chlorideas described in the preparation of Intermediate 1A gave the title esteras white prisms: mp 58-59° C. (hexane) ¹HNMR 400 MHz (CDCl₃) δ (ppm):3.94 (3H, s, OCH₃), 5.1 (2H, s, OCH₂), 7.09-7.69 (8H, m, aromatics).Anal. Calcd for C₁₅H₁₃FO₃: C 69.22, H 5.03. Found: C 69.08, H 4.97.

[0188] Intermediate 3B: 3-(4-Fluorobenzyloxy)-benzoic Acid

[0189] Saponification of methyl 3-(4-fluorobenzyloxy)-benzoate asdescribed in the preparation of Intermediate 1B gave the title acid aswhite needles: mp 145-146° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 5.11 (2H, s, OCH₂), 7.12 (2H, m, aromatics), 7.24 (1H, m,aromatics), 7.45 (3H, m, aromatics), 7.75 (2H, m, aromatics). Anal.Calcd for C₁₄H₁₁FO₃: C 68.29, H 4.50. Found: C 68.39, H 4.43.

[0190] Intermediate 3C: 3-(4-Fluorobenzyloxy)-N-methyl-benzylamine

[0191] Intermediate 3C was prepare from Intermediate 3B using Method II,step 2. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.48 (3H, s, NCH₃), 3.72 (2H, s,NCH₂), 5.05 (2H, s, OCH₂), 6.9-7.45 (8H, m, aromatics). MS (ESI⁺) (m/z):246 (M+H).

[0192] Intermediate 3D:N-{3-(4-Fluorobenzyloxy)-benzyl}-N-methylacetamide

[0193] Intermediate 3D was prepared from Intermediate 3C using MethodVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.15 and 2.16(3H, 2 s, COCH₃), 2.91 and 2.94 (3H, 2 s, NCH₃), 4.49 and 4.55 (2H, 2 s,NCH₂), 5.01 (2H, s, OCH₂), 6.75; 7.42 (8H, m, aromatics). MS (ESI⁺)(m/z) 288 (M+H).

[0194] Intermediate 3E:3-{[3-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0195] Intermediate 3E was prepared from Intermediate 3D using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.99 and 3.01(3H, 2 s, NCH₃), 3.86 and 3.9 (3H, 2 s, OCH₃), 4.55 and 4.62 (2H, 2 s,NCH₂), 5.01 (2H, s, OCH₂), 6.29 (1H, s, CH), 6.7-7.41 (8H, m,aromatics). HRMS (MAB N₂) calculated for C₂₀H₂₀FNO₅ [M⁺]: 373.1325:found: 373.1326.

[0196] Compound 3:3-{[3-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0197] Compound 3 was prepared from Intermediate 3E using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.02 and 3.05 (3H, 2s, NCH₃), 4.58 and 4.65 (2H, 2 s, NCH₂), 5.03 (2H, s, OCH₂ ), 6.38 (1H,s, CH), 6.79-7.43 (8H, m, aromatics). HRMS (MAB N₂) calculated forC₁₉H₁₈FNO₅ [M⁺]: 359.1169: found 359.1170, δ −0.2 ppm.

EXAMPLE 4

[0198] Intermediate 4A: [Bis-(4-chloro-phenyl)-methyl]-methyl-amine

[0199] A solution of 4,4′-dichlorobenzhydryl chloride (3.22 g, 11.85mmol) in a 1.85 M solution of methylamine in tetrahydrofuran (40 ml) washeated at 125° C. in a pressure vessel for 24 h. The cooled reactionmixture was diluted with ethyl acetate, washed with sodium carbonate,brine and dried (magnesium sulfate). Evaporation of the solvent andchromatography of the residue on silica gel (elution toluene-ethylacetate 8:2) gave 2.12 g (67%) of the title amine as a clear oil . ¹HNMR400 MHz (CDCl₃) δ (ppm): 2.57 (3H, s, NCH₃), 4.85 (1H, s, CHbenzhydryl), 7.0-7.53 (8H, m, aromatics). MS (ESI ⁺) (m/z): 266 (M+H).

[0200] Intermediate 4B: N-[Bis-(4-chloro-phenyl)-methyl]-N-methyl-acetamide

[0201] Intermediate 4B was prepared from Intermediate 4A using MethodVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.17 (3H, s,COCH₃), 2.66 and 2.75 (3H, 2 s, NCH₃), 6.13 (1H, s, CH benzhydryl), 7.06and 7.3 (2×4H, m, aromatics).

[0202] Intermediate 4C: 3-{[Bis-(4-chloro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic AcidMethyl Ester

[0203] Intermediate 4C was prepared from Intermediate 4B using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.79 and 2.89(3H, 2 s, NCH₃), 3.88 and 3.92 (3H, 2 s, OCH₃), 6.31, 6.33 and 6.35 (2H,3 s, CH benzhydryl and CH), 7.28 (4H, m, aromatics), 7.37 (4H, m,aromatics). HRMS (ESI⁺) calculated for C₁₉H₁₉C₁₂NO₄ [M+H⁺]: 394.0613:found: 394.0609.

[0204] Compound 4:3-{[Bis-(4-chloro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0205] Compound 4 was prepared from Intermediate 4C using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.80 and 2.89 (3H, 2s, NCH₃), 6.31, 6.37 and 6.41 (2H, 3 s, CH benzhydryl and CH), 7.06-7.17and 7.32-7.43 (8H, m, aromatics ). HRMS (MAB N₂) calculated forC₁₈H₁₅C₁₂NO₄ [M⁺]: 379.0378: found: 379.0374, δ 1.1 ppm.

EXAMPLE 5

[0206] Intermediate 5A: [Bis-(4-fluoro-phenyl)-methyl]-methyl-amine

[0207] A mixture of 4,4′-difluorobenzophenone (2.18 g, 10.0 mmol) inanhydrous ethanol (15 ml) was treated successively with titanium (IV)isopropoxide (5.9 ml, 20.0 mmol), methylamine hydrochloride (1.35 g,20.0 mmol) and triethylamine (2.8 ml, 20.0 mmol).The resulting mixturewas stirred at 22° C. for 18 h and then treated with sodium borohydride(0.57 g, 15.0 mmol). After 6 h at 22° C., the reaction mixture wasquenched by the addition of 2N aqueous ammonia (30 ml) and the resultingprecipitate was filtered and washed with dichloromethane. The organiclayer was collected and extracted with 1N hydrochloric acid. The aqueousphase was then treated with 2N aqueous sodium hydroxide (pH 11) andextracted twice with dichloromethane. The combined extracts were dried(magnesium sulfate) and concentrated. Distillation of the residue invacuo gave 2.12 g (91%) of the title amine as a clear oil : bp 85-90°C./0.2 torr, (bulb to bulb distillation, air bath temperature). ¹HNMR400 MHz (CDCl₃) δ (ppm): 2.40 (3H, s, NCH₃), 4.68 (1H, s, CHbenzhydryl), 7.0 (4H, m, aromatics), 7.35 (4H, m, aromatics). Anal.Calcd for C₁₄H₁₃F₂N: C 72.09, H 5.62, N 6.0. Found: C 71.76, H 5.76, N5.84.

[0208] Intermediate 5B:N-[Bis-(4-fluoro-phenyl)-methyl]-N-methyl-acetamide

[0209] Intermediate 5B was prepared from Intermediate 5A using MethodVIII. Solid: mp 99-100° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃)δ (ppm): mixture of rotamers; 2.20 and 2.21 (3H, 2 s, COCH₃), 2.70 and2.78 (3H, 2 s, NCH₃), 6.18 (1H, s, CH benzhydryl), 7.0-7.25 (8H, m,aromatics). Anal. Calcd for C₁₆H₁₅F₂NO: C 69.81, H 5.49, N 5.09 Found: C69.52, H 5.47, N 5.01.

[0210] Intermediate 5C:3-{[Bis-(4-fluoro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0211] Intermediate 5C was prepared from Intermediate 5B using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.79 and 2.89(3H, 2 s, NCH₃), 3.88 and 3.92 (3H, 2 s, OCH₃), 6.33 and 6.35 (2H, 2 s,CH benzhydryl and CH), 7-7.2 (8H, m, aromatics). MS (ESI⁺) (m/z): 362(M+H).

[0212] Compound 5:3-{[Bis-(4-fluoro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0213] Compound 5 was prepared from Intermediate 5C using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.82 and 2.91 (3H, 2s, NCH₃), 6.36 and 6.41 (1H, 2 s, CH), 6.43 (1H, s, CHbenzhydryl),7.1-7.4 (8H, m, aromatics ). HRMS (MAB N₂ ) calculated forC₁₈H₁₅F₂NO₄ [M⁺]: 347.0969: found: 349.0960, δ 2.6 ppm.

EXAMPLE 6

[0214] Intermediate 6A:N-[Bis-(4-methoxy-phenyl)-methyl]-N-methyl-acetamide

[0215] Intermediate 6A was prepared frombis-(4-methoxy-phenyl)-methyl]-methyl-amine (Cymerman-Craig, et al.Aust. J. Chem. 1955, 8, 385) using Method VIII. ¹HNMR 400 MHz (CDCl₃) δ(ppm): mixture of rotamers; 2.19 and 2.21 (3H, 2 s, COCH3), 2.70 and2.78 (3H, 2 s, NCH₃), 3.81 and 3.82 (3H, 2 s, OCH₃), 6.13 (1H, s, CHbenzhydryl), 6.87 and 7.08 (2×4H, m, aromatics). Anal. Calcd forC₁₈H₂₁NO₃: C 72.22, H 7.07, N 4.68 Found: C 71.99, H 6.88, N 4.65.

[0216] Intermediate 6B:3-{[Bis-(4-methoxy-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester:

[0217] Intermediate 6B was prepared from Intermediate 6A using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.79 and 2.89(3H, 2 s, NCH₃), 3.84, 3.85, 3.87 and 3.92 (9H, 4 s, OCH₃), 6.30, 6.34and 6.37 (2H, 3 s, CH benzhydryl and CH), 6.9-6.93 (4 H, m, aromatics),7.08-7.14 (4H, m, aromatics). HRMS (ESI⁺) calculated for C₂₁H₂₄NO₆[M+H⁺]: 386.16037: found: 386.15890.

[0218] Compound 6:3-{[Bis-(4-methoxy-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid:

[0219] Compound 6 was prepared from Intermediate 6B using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.75 and 2.83 (3H, 2s, NCH₃), 3.77, and 3.78 (6H, 2 s, OCH₃), 6.23, 6.33 and 6.36 (2H, 3 s,CH benzhydryl and CH), 6.83-6.86 (4H, m, aromatics ), 6.88-7.06 (4H, m,aromatics ). HRMS ESI⁻) calculated for C₂₀H₂₀NO₆ [M−H]⁻: 370.12906:found: 370.13003, δ −2.6 ppm.

EXAMPLE 7

[0220] Intermediate 7A:3-(Benzhydryl-methyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester

[0221] Intermediate 7A was prepared fromN-Bis-(phenyl)-methyl]-N-methyl-acetamide from using Method IX. ¹HNMR400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.67 and 2.83 (3H, 2 s,NCH₃), 3.79 and 3.83 (3H, 2 s, OCH₃), 6.28 (1H, s, CH benzhydryl), 6.3and 6.31 (1H, 2 s, CH), 7-7.4 (10H, m, aromatics).

[0222] Compound 7: 3-(Benzhydryl-methyl-carbamoyl)-2-hydroxy-acrylicAcid:

[0223] Compound 7 was prepared from Intermediate 7A using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.82 and 2.91 (3H, 2s, NCH₃), 6.41 (1H, s, CH benzhydryl), 6.37 and 6.43 (1H, 2 s, CH),7.1-7.4 (10H, m, aromatics ). HRMS (MAB N₂) calculated for C₁₈H₁₇NO₄[M⁺]: 311.1157: found 311.1154, δ 1 ppm.

EXAMPLE 8

[0224] Intermediate 8A: 2,2-Bis-(4-fluoro-phenyl)-N-methyl-acetamide

[0225] A mixture of bis-(4-fluorophenyl)-acetic acid (8.07 g, 32.5 mmol)(prepared using the procedure of Takahashi, Y. et al., Chem. Lett.,1985, 1733.), in dichloromethane (30 ml) was treated at 22° C. withoxalyl chloride (5.5 ml, 65.0 mmol) and a drop of N,N-dimethylformamide.After 18h at 22° C., the solvent and excess reagent were evaporatedunder reduce pressure. The residual oil was then dissolved in drytetrahydrofuran (10 ml) and added dropwise and under good stirring to acold (0-5° C.) mixture of methylamine hydrochloride (10.9 g, 0.16 mol),sodium hydroxide (6 g) in water (50 ml) and tetrahydrofuran (100 ml).After 1 h at 22° C., the reaction mixture was diluted with ethylacetate, washed successively with water, 1N hydrochloric acid, saturatedsodium bicarbonate, brine and dried (magnesium sulfate). Evaporation ofthe solvent and crystallization of the residue in ethyl acetate gave7.75 g (91%) of the title material as white needles: mp 179-180° C.¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.86 (3H d, J=5.1 Hz, NCH₃), 4.87 (1H, s,CH) 5.65 (1H, broad, NH), 7.04 and 7.23 (2×4H, 2 m, aromatics). Anal.Calcd for C₁₅H₁₃F₂NO: C 68.96, H 5.02, N 5.36. Found: C 68.88, H 4.49, N5.75.

[0226] Intermediate 8B: [2,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-amine

[0227] A mixture of Intermediate 8A (8.68 g, 33.2 mmol) intetrahydrofuran (50 ml) was treated with boron trifluoride diethyletherate (4.2 ml, 33.2 mmol) and heated under reflux for 15 min. Theresulting homogeneous solution was cooled at 22° C. and treated withborane-methyl sulfide complex (4.5 ml, 4.5 mmol) added dropwise over 5min. The solution was then heated under reflux for 30 min. Thetetrahydrofuran was then distilled and the residue was maintained at110° C. for another hour. The cooled mixture was then treated dropwisewith 6N hydrochloric acid (15 ml) and heated under reflux for 1 h. Themixture was cooled to 0-5° C. and 6N sodium hydroxide solution (30 ml)was added. The aqueous mixture was extracted with ether (4×), thecombined extracts were dried (anhydrous sodium carbonate) andconcentrated under reduce pressure. Distillation of the residue in vacuogave 7.66 g (93%) of the title amine as a clear oil: bp 90-105° C./0.2torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz(C₆D₆) δ (ppm): 2.27 (3H, s, NCH₃), 2.93 (2H, d, J=7.6 Hz, CH₂), 3.96(1H, t, J=7.6 Hz, CH) and 6.91 (8H, m, aromatics). MS (ESI⁺) (m/z): 248(M+H) Anal. Calcd for C₁₅H₁₅F₂N-0.25 H₂O: C 71.55, H 6.21, N 5.56.Found: C 71.67, H 5.86, N 5.59.

[0228] Intermediate 8C:N-[2,2-Bis-(4-fluoro-phenyl)-ethyl]-N-methyl-acetamide

[0229] Intermediate 8C was prepared from Intermediate 8B using MethodVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.72 and 2.01(3H, 2 s, COCH₃), 2.71 and 2.87 (3H, 2 s, NCH₃), 3.88 and 3.95 (2H, 2d,J=7.6 Hz and J=8.0 Hz, CH₂), 4.31 and 4.40 (1H, 2t, J=7.6 Hz and J=8.0Hz, CH), 6.98;7.25 (8H, m, aromatics). MS (ESI⁺) (m/z): 290 (M+H).

[0230] Intermediate 8D:3-{[2,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0231] Intermediate 8D was prepared from Intermediate 8C using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.78 and 2.84(3H, 2 s, NCH₃), 3.88 and 3.90 (3H, 2 s, OCH₃), 3.96 and 4.03 (2H, 2d,J=8 Hz, CH₂), 4.23 and 4.42 (1H, 2t, J=8.0 Hz, CH), 5.95 and 6.14 (1H, 2s, CH), 7.0-7.24 (8H, m, aromatics). MS (ESI⁺) (m/z): 376 (M+H).

[0232] Compound 8:3-{[2,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0233] Compound 8 was prepared from Intermediate 8D using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.77 and 2.84 (3H, 2s, NCH₃), 3.94 and 4.02 (2H, 2 d, J=8.1 Hz and J=8.2 Hz, CH₂), 4.21 and4.40 (1H, 2t, J=8.1 Hz and J=8.2 Hz, CH), 6.0 and 6.18 (1H, 2 s, CH),6.98-7.25 (8H, m, aromatics) HRMS (ESI⁻) calculated for C₁₉H₁₆F₂NO₄[M−H]⁻: 360.1036: found 360.1049, δ−0.5 ppm.

EXAMPLE 9

[0234] Intermediate 9A: 2,2-Bis-(4-chorophenyl)-N-methyl-ethylamine

[0235] Intermediate 9A was prepared from2,2-bis-(4-chlorophenyl)-N-methylacetamide using Method II, step II.¹HNMR 400 MHz (C₆D₆) δ (ppm): 2.26 (3H, s, NCH₃), 2.89 (2H, d, J=7.1 Hz,CH₂), 3.87 (1H, t, J=7.1 Hz, CH), 6.86 (4H, d, J=8.3 Hz, aromatics) and7.19 (4H, d, J=8.3 Hz, aromatics).

[0236] Intermediate 9B:N-{2,2-Bis-(4-chlorophenyl)-ethyl}-N-methylacetamide

[0237] Intermediate 9B was prepared from Intermediate 9A using MethodVIII. Solid: mp 103-104° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm) mixture of rotamers; 1.92 (3H, s, COCH₃), 2.63 and 2.78(3H, 2 s, NCH₃), 3.79 and 3.85 (2H, 2d, J=7.6 Hz and J=8.0 Hz, CH₂),4.10 and 4.30 (1H, 2t, J=7.6 Hz and J=8.0 Hz, CH), 7.03-7.25 (8H, m,aromatics). Anal. Calcd for C₁₇H₁₇Cl₂NO: C 63.37, H 5.32, N 4.35. Found:C 63.09, H 5.34, N 4.29. MS (ESI⁺) (m/z): 322 (M+H).

[0238] Intermediate 9C:3-{[2,2-Bis-(4-chloro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0239] Intermediate 9C was prepared from Intermediate 9B using MethodIX. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.81 and 2.88(3H, 2 s, NCH₃), 3.92 and 3.93 (3H, 2 s, OCH₃), 3.99 and 4.06 (2H, 2d,J=7.6 Hz and J=8.1 Hz, CH₂), 4.23 and 4.45 (1H, 2t, J=7.6 Hz and J=8.1Hz, CH), 5.95 and 6.17 (1H, 2 s, CH), 7.16-7.37 (8H, m, aromatics). MS(ESI⁺) (m/z) 408 (M+H).

[0240] Compound 9:3-{[2,2-Bis-(4-chloro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0241] Compound 9 was prepared from Intermediate 9C using Method XI.¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.78 and 2.84 (3H, 2s, NCH₃), 3.95 and 4.02 (2H, 2 d, J=8.1 Hz and J=8.3 Hz, CH₂), 4.18 and4.38 (1H, 2t, J=8.1 Hz and J=8.3 Hz, CH), 6.0 and 6.2 (1H, 2 s, CH),7.1-7.31 (8H, m, aromatics ). HRMS (ESI⁻) calculated for C₁₉H₁₆C₁₂NO₄[M−H]⁻: 392.0456 : found: 392.0475, 8-4.8 ppm.

EXAMPLE 10

[0242] Intermediate 10A: N-(2-Chloro-benzyl)-N-methyl-acetamide

[0243] 2-Chlorobenzyl bromide (1.37 g, 6.67 mmol) was dissolved in 5 mlof THF. To this was added 5 ml of 40% (aq.) methylamine and theresulting mixture stirred 15 min. The reaction mixture was transferredto a separatory funnel, diluted with 100 ml H₂O and extracted with 100ml of ethyl acetate. The organic solution was washed with brine, driedover Na₂SO₄ then filtered and the solvent removed to yield 1.21 g oil.The crude product was purified by column chromatography (5×6.5 cm SiO₂,2-10% EtOH/CH₂Cl₂) to yield 710 mg (68% yield) oil. LC/MS (M+H) calcdfor C₈H₁₁ClN: 156.06; found: 155.99.

[0244] The amine (710 mg, 4.6 mmol) synthesized above was dissolved in30 ml CH₂Cl₂. Satd. (aq.) NaHCO₃ was added followed by CH₃COCl (0.36 ml,5.0 mmol) and the resulting mixture stirred for 1 h. The organic layerwas separated, washed with brine dried over Na₂SO₄ then filtered and thesolvent removed to yield 900 mg (>99% yield) oil as a pure product.LC/MS (M+H) calcd for C₁₀H₁₃ClNO: 198.06; found: 198.02. ¹H NMR and ¹³CNMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.10 (s), 2.19 (s), 2.97 (s), 4.59 (s), 4.73 (S), 7.10-7.41(overlapping m, 4). ¹³C NMR (125 MHz, CDCl₃) δ: 21.33, 21.82, 34.06,36.03, 48.06, 52.22, 126.79, 127.10, 127.36, 128.54, 128.83, 129.10,129.57, 129.91, 132.84, 133.59, 133.96, 134.67, 170.99, 171.41. LC/MS(M+H) calcd for C₁₀H₁₃ClNO: 198.06; found: 198.02. Anal calcd forC₁₀H₁₂ClNO: C, 60.76; H, 6.11; N, 7.08; Cl, 17.93; found: C, 60.53; H,6.15; N, 7.04; Cl, 17.81.

[0245] Intermediate 10B:3-[(2-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0246] Intermediate 10A (1.96 g, 9.92 mmol) was dissolved in 20 ml ofanhydrous THF under an N₂ atmosphere then cooled to −78° C. To this wasadded 30 ml of 1M LiHMDS (lithium bis(trimethylsilyl)amide) and thereaction mixture stirred for 20 min. at which point dimethyl oxalate(1.76 g, 14.9 mmol) dissolved in 8 ml of THF was added. The reaction wasallowed to continue at −78° C. for 20 min. then warmed to 0° C. andstirred an additional 45 min. 1 N HCl was added and the resultingmixture extracted with EtOAc. The organic solution was washed withbrine, dried over Na₂SO₄ then filtered and the solvent removed to yield2.80 g oil. The crude product was purified by reverse phase preparativeHPLC (C₁₈, MeOH/H₂O (0.1% TFA)-gradient) to yield 382 mg (14% yield)oil. LC/MS (M+H) calcd for C₁₃H₁₅NO₄Cl: 284.06; found 284.01 ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 3.06 (s), 3.07 (s), 3.85 (s), 3.91 (s), 4.68 (s), 4.81 (s), 6.19 (s),6.34 (s), 7.07-7.44 (overlapping m, 4).

[0247] Compound 10:3-[(2-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0248] Compound 10 was prepared from Intermediate 10B using Method X.More specifically, to a solution of Intermediate 10B (95 mg, 0.33 mmol)dissolved in 0.4 ml of MeOH was added 0.4 ml of 1N NaOH. After stirringfor 1 h, 0.4 ml of 1N HCL was added and the resulting mixture extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄then filtered and the solvent removed to yield 100 mg oil. The crudeproduct was purified by reverse phase preparative HPLC (C₁₈, MeOH/H₂O(0.1%TFA)) to yield 47 mg (52% yield) solid. mp=84-86° C. LC/MS (M+H)calcd for C₁₂H₁₃ClNO₄: 270.05; found: 269.96. HRMS (M+H) calcd forC₁₂H₁₃ClNO₄: 270.0533; found: 270.0534. ¹H NMR and ¹³C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.08(s), 4.69 (s), 4.82 (s), 6.27 (s), 6.41 (s), 7.06-7.45 (overlapping m,4). ¹³C NMR (125 MHz, CDCl₃) δ: 34.00, 35.36, 48.34, 51.18, 93.44,127.20, 127.33, 127.48, 128.97, 129.10, 129.35, 129.83, 130.08, 132.70,133.02, 133.33, 133.62, 159.11, 159.22, 164.65, 164.73, 171.21, 171.60.

EXAMPLE 11

[0249] Intermediate 11A; N,N-bis-(4-fluoro-benzyl)-acetamide

[0250] To 4-flourobenzylamine (1.17 g, 9.4 mmol) dissolved in 5 mL ofTHF was added 4-fluorobenzyl-bromide (0.88 g, 4.7 mmol) dropwise. Thereaction was stirred overnight resulting in the formation of a whitesolid. After filtering off the solid solvent was removed to yield 1.08 gcrude di-(4-fluorobenzyl) amine. To this was added 19 mL of CH₂Cl₂ and19 mL of saturated (aq.) NaHCO₃. Acetyl chloride (0.67 mL, 9.4 mmol) wasadded to the rapidly stirring mixture and the reaction allowed toproceed overnight. The mixture was diluted with CH₂Cl₂, transferred to aseparatory funnel. The organic layer was separated, washed with satd(aq.) NaCl, dried over Na₂SO₄ and the solvent removed to yield 1.01 goil. The product was purified by column chromatography (4×7 cm SiO₂,20-40% EtOAc/Hexanes) to yield 603 mg (55% yield) oil. LC/MS (M+H) calcdfor C₁₄H₁₄NF₂: 276.12, found: 276.13. HRMS (M+H) calcd for C₁₄H₁₄NF₂:276.1200, found: 276.1192. Anal calcd for C₁₆H₁₅F₂NO: C, 69.80; H, 5.49;N, 5.08; found: C, 59.53; H, 5.41; N, 5.06. ¹H NMR (500 MHz, DMSO) δ:2.10 (s, 3), 4.45 (s, 2), 4.49 (s, 2), 7.18-7.27 (m, 8). ¹³C NMR (125MHz, DMSO) δ; 21.34, 47.04, 50.04, 114.90, 115.07, 115.27, 115.45,128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25,160.33, 162.17, 162.27, 170.22.

[0251] Intermediate 11B:3-[Bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0252] Intermediate 11B was prepared from Intermediate 11A by the samemethod that Intermediate 10B was prepared from Intermediate 10A. Solid,mp 117-118° C. LC/MS (M+H) calcd for C₁₉H₁₈F₂NO₄: 362.11, found: 362.03.HRMS (M+H) calcd for C₁₉H₁₈F₂NO₄: 362.1204, found: 362.1187. Anal. calcdfor C₁₉H₁₇NO₄F₂: C, 63.15; H, 4.74; N, 3.87; found: C, 62.97; H, 4.72;N, 3.81. ¹H NMR (500 MHz, CDCl₃) δ: 3.87 (s, 3), 4.46 (s, 2), 4.58 (s,2), 6.32 (s, 1), 7.00-7.26 (m, 8). ¹³C NMR (125 MHz, CDCl₃) δ: 47.34,49.35, 53.03, 93.34, 115.56, 115.83, 116.00, 116.18, 128.45, 128.52,130.03, 130.10, 131.09, 131.93, 131.96, 160.29, 161.44, 161.51, 163.10,163.41, 163.47, 171.36.

[0253] Compound 11:3-[Bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0254] Compound 11 was prepared from Intermediate 11B by Method XI.Solid mp >147° C. (decomposition). LC/MS (M+H) calcd for C₁₈H₁₆F₂NO₄:348.10, found 347.98. HRMS (M−H) calcd for C₁₈H₁₄F₂NO₄: 346.089, found346.088. ¹H NMR (500 MHz, DMSO) δ: 4.61 (s, 2), 4.67 (s, 2), 6.25 (s,1), 7.12-7.35 (overlapping m). ¹³C NMR (125 MHz, DMSO) δ: 47.94, 49.49,93.27, 115.11, 115.28, 115.38, 115.55, 128.46, 128.52, 129.88, 129.94,132.76, 132.78, 132.93, 132.96, 10.35, 163.27, 171.25.

EXAMPLE 12

[0255] Intermediate 12A: N-(2-bromo-benzyl)-N-methyl-acetamide

[0256] Intermediate 12A was prepared from ortho-bromobenzyl bromide byMethod V. Anal calcd for C₁₀H₁₂BrNO: C, 49.60; H, 4.99; N, 5.78; Br,33.00; found: C, 49.40; H, 4.95; N, 5.75; Br, 32.98. LC/MS (M+H) calcdfor C₁₀H₁₃BrNO: 242.02; found: 243.96. ¹H NMR shows a mixture ofrotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.09 (s), 2.19(s), 2.98 (s), 2.99 (s), 4.55 (s), 4.71 (s), 7.08-7.60 (overlapping m,4). ¹H NMR (300 MHz, DMSO, T=393 K) δ: 2.06 (s, 3), 2.92 (s, 3), 4.58(s, 2), 7.21 (m, 2), 7.37 (m, 1), 7.60 (d, 1, J=8).

[0257] Intermediate 12B:3-[(2-Bromo-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0258] Intermediate 12B was prepared from Intermediate 12A using MethodIX. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.06 (s), 3.07 (s), 3.85 (s), 3.91 (s), 4.65 (s), 4.79(s), 7.17-7.35 (overlapping m, 4).

[0259] Compound 12:3-[(2-Bromo-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0260] Compound 12 was prepared from Intermediate 12B using Method X.HRMS (M+H) calcd for C₁₂H₁₃BrNO₄: 314.0028; found: 314.0023. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.08 (s, 3), 4.66 (s), 4.80 (s), 6.25 (s), 6.42 (s), 7.04-7.63(overlapping m, 4). ¹³C NMR (125 MHz, CDCl₃) δ: 34.09, 35.37, 50.85,53.70, 93.21, 122.84, 123.59, 127.17, 127.97, 128.11, 128.77, 129.38,129.63, 133.17, 133.40, 134.13, 134.82, 159.00, 159.14, 171.22, 171.64.

EXAMPLE 13

[0261] Intermediate 13A: N-benzyl-N-phenethyl-acetamide

[0262] N-benzyl-2-phenethylamine (2.2 g, 10 mmol) was dissolved in 7 mLof CH₂Cl₂. To this was added 7 mL of satd (aq.) NaHCO₃ followed byacetyl chloride (0.88 g, 11 mmol) and the resulting mixture stirred for40 min. The organic layer was separated, dried over Na₂SO₄ filtered andthe solvent removed to yield 2.60 g (100%) oil. LC/MS (M+H) calcd forC₁₇H₂₀NO: 254.15; found: 254.07. ¹H NMR and ¹³C NMR show a mixture ofrotamers at room temperature. ¹H NMR (500 MHz, CDCl₃), δ: 2.04 (br s),2.14 (br s), 2.81 (br m), 2.87 (br m), 3.44 (br m), 3.58 (br m), 4.36(s), 4.62 (s), 7.11-7.36 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃)δ: 21.19, 21.80, 33.99, 34.87, 48.18, 48.28, 49.49, 52.75, 126.34,126.81, 127.44, 127.65, 128.18, 128.52, 128.64, 128.73, 128.80, 128.85,128.94, 136.74, 137.56, 138.17, 139.24, 170.81, 171.07.

[0263] Intermediate 13B:3-(Benzyl-phenethyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester

[0264] Intermediate 13B was prepared from Intermediate 13A using MethodIX. LC/MS (M+H) calcd for C₂₀H₂₂NO₄: 340.03; found: 340.15. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.84 (t, J=7), 2.90 (t, J=7), 3.52 (t, J=7), 3.63 (t, J=7),3.86 (s), 3.90 (s), 4.41(s), 4.56 (s), 6.22 (s), 6.26 (s), 7.13-7.37(overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 33.94, 35.38, 48.40,48.94, 51.84, 52.97, 93.72, 126.62, 126.65, 126.97, 127.81, 128.02,128.05, 128.67, 128.77, 128.83, 128.90, 129.03, 135.84, 136.56, 137.64,138.64, 159.52, 159.80, 163.31, 170.88, 171.28.

[0265] Compound 13: 3-(Benzyl-phenethyl-carbamoyl)-2-hydroxy-acrylicAcid

[0266] Compound 13 was prepared from Intermediate 13B using Method X.LC/MS (M+H) calcd for C₁₉H₂₀NO₄: 326.14; found: 326.01. HRMS (M−H) calcdfor C₁₉H₁₈NO₄: 324.1236; found: 324.1234. ¹H NMR and ¹³C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.85(t, J=7), 2.90 (t, J=7), 3.54 (t, J=7), 3.65 (t, J=7), 4.41 (s), 4.56(s), 6.26 (s), 6.33 (s), 7.11-7.40 (overlapping m, 10). ¹³C NMR (125MHz, CDCl₃) δ: 33.91, 35.30, 48.59, 49.05, 49.10, 51.97, 93.76, 93.86,126.69, 128.09, 128.28, 128.72, 128.78, 128.80, 128.88, 128.97, 129.09,135.55, 136.29, 137.45, 138.49, 158.84, 159.27, 165.08, 165.15, 170.85,171.26.

EXAMPLE 14

[0267] Intermediate 14A: N,N-dibenzyl-acetamide

[0268] Intermediate 14A was prepared from dibenzylamine by the samemethod as Intermediate 12A. LC/MS (M+H) calcd f or C₁₆H₁₈NO: 240.14;found: 240.03. ¹H NMR (500 MHz, CDCl₃) δ: 3.23 (s, 3), 4.47 (s, 2), 4.61(s, 2), 7.16-7.39 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ:21.70, 48.02, 50.78, 126.42, 127.46, 127.68, 128.34, 128.63, 129.01,136.41, 137.31, 171.22.

[0269] Intermediate 14B: 3-Dibenzylcarbamoyl-2-hydroxy-acrylic AcidMethyl Ester

[0270] Intermediate 14B was prepared from Intermediate 14A using MethodIX. LC/MS (M+H) calcd for C₁₉H₂₀NO₄: 326.14; found: 326.01. ¹H NMR (500MHz, CDCl₃) δ: 3.87 (s, 3), 4.51 (s, 2), 4.64 (s, 2), 6.36 (s, 1),7.17-7.40 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 48.02, 49.95,53.00, 93.62, 126.78, 127.85, 128.08, 128.13, 128.25, 128.77, 128.85,129.00, 129.10, 135.50, 136.24, 160.05, 163.22, 171.43.

[0271] Compound 14: 3-Dibenzylcarbamoyl-2-hydroxy-acrylic Acid

[0272] Compound 14 was prepared from Intermediate 14B using Method X.LC/MS (M+H) calcd for C₁₈H₁₈NO₄: 312.12; found: 312.07. HRMS (M−H) calcdfor C₁₈H₁₆NO₄: 310.1079; found: 310.1075. ¹H NMR (500 MHz, CDCl₃) δ:4.52 (s, 2), 4.66 (s, 2), 6.43 (s, 1), 7.16-7.43 (overlapping m, 10).¹³C NMR (125 MHz, CDCl₃) δ: 48.30, 50.07, 93.24, 126.77, 127.98, 128.20,128.27, 128.90, 129.15, 135.12, 135.90, 159.35, 164.50, 171.43.

EXAMPLE 15

[0273] Intermediate 15A:N-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-N-methyl-acetamide

[0274] Intermediate 15A was prepared from3-(bromomethyl)-5-chlorobenzothiophene by Method V. LC/MS (M+H) calcdfor C₁₂H₁₃NOClS: 254.04; found: 253.92. ¹H NMR and ¹³C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.17(s, 3), 2.93 (s), 3.05 (s), 4.70 (s), 4.79 (s), 7.22-7.88 (overlappingm, 5). ¹³C NMR (125 MHz, CDCl₃) δ: 1.26, 21.92, 34.17, 35.27, 44.22,49.43, 120.77, 122.04, 123.76, 124.18, 125.16, 125.42, 126.79, 131.85,138.66, 139.30, 170.78.

[0275] Intermediate 15B:3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylicAcid Methyl Ester

[0276] Intermediate 15B was prepared from Intermediate 15A using MethodIX. LC/MS (M+H) calcd for C₁₅H₁₅NO₄ClS: 340.04; found: 339.89. HRMS(M+H) calcd for C₁₅H₁₅NO₄ClS: 340.0410; found: 340.0410. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.03(s), 3.13 (s), 3.85 (s), 3.90, 4.77 (s), 4.87 (s), 6.28 (s), 6.30 (s),7.23-7.86 (overlapping m, 4).

[0277] Compound 15:3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylicAcid

[0278] Compound 15 was prepared from Intermediate 15B using Method X.LC/MS (M+H) calcd for C₁₄H₁₃NO₄ClS: 326.03; found: 326.08. HRMS (M−H)calcd for C₁₄H₁₁NO₄ClS: 324.0097; found: 324.0104. ¹H NMR and ¹³C NMRshow a mixture of rotamers at room temperature. ¹H NMR (500 MHz, DMSO)δ: 3.05 (s), 4.85 (s), 4.97 (s), 6.27 (s), 6.30 (s), 7.41-8.07(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.68, 34.46, 43.62, 47.54,93.00, 93.32, 121.33, 121.38, 121.61, 124.55, 124.64, 124.71, 125.55,128.15, 129.41, 129.52, 130.79, 131.21, 138.37, 138.45, 138.99, 139.05,160.02, 160.12, 163.38, 163.45, 170.50, 171.05.

EXAMPLE 16

[0279] Intermediate 16A: N-(4-fluoro-benzyl)-N-methyl-acetamide

[0280] Intermediate 16A was prepared from 4-fluorobenzyl bromide byMethod IV. LC/MS (M+H) calcd for C₁₀H₁₃FNO: 182.09; found: 182.10. HRMS(M+H) calcd for C₁₀H₁₄NFNO; 182.0891; found: 182.0979. ¹H NMR (500 MHz,DMSO) δ: 2.04 (s), 2.05 (s), 2.77 (s), 2.90 (s), 4.46 (s), 4.53 (s),7.13-7.28 (m, 4). ¹³C NMR (125 MHz, DMSO) δ: 21.16, 21.47, 32.85, 35.24,48.81, 52.40, 114.97, 115.14, 115.30, 115.47, 128.52, 128.59, 129.38,129.44, 133.58, 133.60, 134.01, 134.03, 160.23, 160.33, 162.16, 162.26,169.70, 169.84.

[0281] Intermediate 16B:3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0282] Intermediate 16B was prepared from Intermediate 16A using MethodIX. HRMS (M+H) calcd for C₁₃H₁₅NO₄F: 268.0985; found: 268.0983. Analcalcd for C₁₃H₁₄NO₄F: C, 58.42; H, 5.28; N, 5.24; found: C, 58.48; H,5.21; N, 5.26. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. LC/MS (M+H) calcd for C₁₃H₁₅FNO₄: 268.09, found: 268.15. ¹HNMR (500 MHz, CDCl₃) δ: 3.00 (s, 3), 3.86 (s), 3.89 (s), 4.55 (s), 4.61(s), 6.29 (s) 6.31, 7.00-7.24 (overlapping m, 4). ¹³C NMR δ: 33.43,34.79, 49.97, 52.63, 52.97, 93.27, 93.55, 115.63, 115.80, 115.95,116.13, 128.36, 128.42, 129.71, 129.78, 131.32, 132.03, 159.70, 161.40,163.25, 163.35, 170.93, 171.16.

[0283] Compound 16:3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0284] Compound 16 was prepared from Intermediate 16B using Method XI.HRMS (M−H) calcd for C₁₂H₁₁NO₄F: 252.0672; found: 252.0666. Anal calcdfor C₁₂H₁₂NO₄F: C, 56.91; H, 4.77; N, 5.53; found: C, 57.22; H, 4.78; N,5.56. LC/MS (M+H) calcd for C₁₂H₁₃FNO₄: 254.08, found: 254.05. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ 3.02 (s, 3), 4.57 (s), 4.63 (s), 6.36 (s), 6.39, 7.02-7.26(overlapping m, 4).

EXAMPLE 17

[0285] Intermediate 17A: N-benzyl-N-methyl-acetamide

[0286] Intermediate 17A was prepared from N-methyl-benzylamine usingMethod IV. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.20 (s), 2.95 (s), 2.97 (s),4.56 (s), 4.62 (s), 7.19-7.41 (overlapping m). ¹³C NMR (125 MHz, CDCl₃)δ: 21.42, 21.80, 33.82, 35.58, 50.68, 54.29, 126.33, 127.41, 127.70,128.07, 128.63, 128.99, 136.46, 137.26, 170.88, 171.19.

[0287] Intermediate 17B: 3-(Benzyl-methyl-carbamoyl)-2-hydroxy-acrylicAcid Methyl Ester

[0288] Intermediate 17B was prepared from Intermediate 17A using MethodIX. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.02 (s), 3.86 (s), 3.90 (s), 4.60 (s), 4.66 (s), 6.31(s), 6.34 (s), 7.18-7.40 (overlapping m).

[0289] Compound 17: 3-(Benzyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0290] Compound 17 was prepared from Intermediate 17B using Method X.HRMS (M−H) calcd for C₁₂H₁₂NO₄: 234.0766; found: 234.0765. ¹H NMR showsa mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:3.02 (s), 3.04 (s), 4.59 (s), 4.67 (s), 6.36 (s), 6.40 (s), 7.17-7.39(overlapping m).

EXAMPLE 18

[0291] Intermediate 18A:N-(2-Chloro-benzyl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide

[0292] Intermediate 18A was prepared from 2(-4-fluorophenyl)-ethylamineand 2-chlorobenzylbromide using Method VI. LC/MS (M+H) calcd forC₁₇H₁₈ClFNO: 306.10; found: 306.00. ¹H NMR shows a mixture of rotamersat room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.05 (s), 2.10 (s), 2.84(m), 3.44 (m), 3.55 (m), 4.46 (s), 4.77 (s), 6.99 (m), 7.13 (m), 7.22(m), 7.38 (m).

[0293] Intermediate 18B:3-{(2-Chloro-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0294] Intermediate 18B was prepared from Intermediate 18A using MethodIX. HRMS (M+H) calcd for C₂₀H₂₀NO₄ClF: 392.1065; found: 392.1053. Analcalcd for C₂₀H₁₉NO₄ClF: C, 61.30; H, 4.88; N, 3.57; found: C, 61.33; H,4.86; N, 3.50. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.87 (m), 3.53 (m), 3.60 (m),3.85 (s), 3.91 (s), 4.53 (s), 4.74 (s), 6.14 (s), 6.20 (s), 6.97 -7.42(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.12, 34.62, 46.17, 48.55,49.36, 49.52, 52.98, 53.01, 93.43, 115.41, 115.58, 115.68, 115.85,127.36, 127.41, 127.44, 129.10, 129.26, 129.39, 129.73, 129.98, 130.21,130.27, 130.33, 132.96, 133.19, 133.59, 133.98, 159.71, 160.04, 160.77,160.95, 162.72, 162.91, 163.20, 171.08, 171.64.

[0295] Compound 18:3-{(2-Chloro-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylicAcid

[0296] Compound 18 was prepared from Intermediate 18B using Method X.HRMS (M−H) calcd for C₁₉H₁₆NO₄ClF: 376.0752; found: 376.0761. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.87 (m), 3. 53 (dd, J=7, 7), 3. 62 (dd, J=7, 9), 4.55 (s),4.75 (s), 6.23 (s), 6.27 (s), 6.97-7.43 (overlapping m). ¹³C NMR (125MHz, CDCl₃) δ: 33.07, 34.53, 46.32, 48.67, 49.40, 49.61, 93.27, 115.46,115.63, 115.75, 115.92, 127.40, 127.44, 129.25, 129.42, 129.45, 129.80,130.08, 130.20, 130.27, 130.29, 130.35, 132.82, 133.02, 133.64, 133.67,158.90, 159.30, 160.80, 160.99, 162.75, 162.95, 171.06, 171.61.

EXAMPLE 19

[0297] Intermediate 19A: N-(2-Chlorobenzyl)-N-(4-fluorobenzyl)-acetamide

[0298] Intermediate 19A was prepared from 2-chlorobenzylamine and4-fluorobenzylbromide using Method VI. LCMS (M+H) calcd for C₁₆H₁₆FNO:292.08; found: 292.01. ¹H NMR and ¹³C NMR show a mixture of rotamers atroom temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.15 (s), 2.24 (s), 4.47(s), 4.51 (s), 4.56 (s), 4.73 (s), 6.97-7.40 (overlapping m, 8). ¹³C NMR(125 MHz, CDCl₃) δ: 21.52, 21.62, 45.86, 48.04, 49.09, 50.93, 115.40,115.57, 115.82, 115.99, 126.92, 127.10, 127.33, 127.97, 128.04, 128.70,128.93, 129.50, 129.58, 129.98, 130.02, 130.09, 131.99, 132.02, 132.91,132.93, 132.99, 133.65, 133.67, 134.54, 161.30, 163.25, 171.29, 171.52.

[0299] Intermediate 19B:3-[(2-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0300] Intermediate 19B was prepared from Intermediate 19A using MethodIX. HRMS (M+H) calcd for C₁₉H₁₈ClFNO₄: 378.0908; found: 378.0908. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.85 (s), 3.88 (s), 4.53 (s), 4.60 (s), 4.61 (s), 4.78(s), 6.19 (s), 6.37 (s), 7.00-7.42 (overlapping m). ¹³C NMR (125 MHz,CDCl₃) δ: 45.88, 48.06, 48.08, 50.07, 53.00, 53.04, 53.45, 93.29, 93.36,115.63, 115.80, 115.92, 116.10, 127.29, 127.41, 128.42, 128.48, 129.09,129.24, 129.26, 129.77, 130.03, 130.07, 130.14, 131.16, 131.92, 132.81,133.05, 133.58, 133.66, 160.29, 160.31, 161.47, 163.05, 163.11, 163.43,171.62, 171.80.

[0301] Compound 19:3-[(2-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0302] Compound 19 was prepared from Intermediate 19B using Method X.HRMS (M−H) calcd for C₁₈H₁₄NO₄ClF: 362.0595; found: 362.0604. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 4.54(s), 4.60 (s), 4.62 (s), 4.79 (s), 6.27 (s), 6.44 (s),7.01-7.42 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 46.09, 48.17,48.27, 50.15, 93.43, 93.56, 115.70, 115.87, 116.00, 116.17, 127.26,127.32, 127.44, 128.42, 128.49, 129.23, 129.30, 129.40, 129.83, 130.11,130.18, 130.86, 130.88, 131.61, 131.63, 132.48, 133.08, 133.29, 133.69,159.29, 159.35, 161.53, 164.31, 171.55, 171.71.

EXAMPLE 20

[0303] Intermediate 20A:N-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide

[0304] Intermediate 20A was prepared from 2-(4-fluoro-phenyl)-ethylamineand 3-bromomethyl-5-chlorobenzo{b}thiophene using Method VI. HRMS (M+H)calcd for C₁₉H₁₈NOClFS: 362.0782; found: 362.0776. ¹H NMR and ¹³C NMRshow a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 2.05 (s), 2.16 (s), 2.73 (t, 8), 2.87 (t, J=8), 3.42 (t, J=8), 3.63(t, J 8), 4.52 (s), 4.79 (s), 6.96-7.82 (overlapping m). ¹³C NMR (125MHz, CDCl₃) δ: 21.37, 21.68, 33.40, 34.23, 41.90, 47.94, 48.48, 49.26,115.31, 115.47, 115.65, 115.82, 120.74, 121.88, 123.86, 124.19, 124.42,125.22, 125.45, 126.84, 130.14, 130.20, 130.22, 130.28, 130.90, 130.96,131.22, 132.01, 133.68, 133.71, 134.58, 134.60, 138.27, 138.64, 139.18,139.31, 160.85, 162.80, 170.58, 170.94.

[0305] Intermediate 20B:3-{(5-Chloro-benzo[b]thiophen-3-ylmethyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0306] Intermediate 20B was prepared from Intermediate 20A using MethodIX. HRMS (M+H) calcd for C₂₂H₁₉NO₄SFCl: 448.0786; found: 448.0777. Analcalcd for C₂₂H₁₈NO₄SFCl: C, 58.99; H, 4.27; N, 3.12; found: C, 59.36; H,4.22; N, 3.08. ¹H NMR and ¹³C NMR show a Mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.75(t, J=7), 2.90(dd, J=8, 8),3.51(t, J=7), 3.68(dd, J=8, 8), 3.84 (s), 3.91 (s), 4.57 (s), 4.75 (s),6.18 (s), 6.21 (s), 6.97-7.80 (overlapping m). ¹³C NMR (125 MHz, CDCl₃)δ: 33.34, 34.68, 42.60, 46.91, 48.65, 53.01, 53.04, 93.33, 93.64,115.48, 115.65, 115.69, 115.75, 115.86, 115.92, 120.76, 121.67, 123.97,124.22, 125.40, 125.56, 127.35, 130.21, 130.28, 130.91, 131.04, 131.12,133.19, 134.03, 138.16, 138.65,139.03, 139.11, 159.82, 160.18, 160.96,162.92, 163.09, 163.18, 170.83, 171.40.

[0307] Compound 20:3-{(5-Chloro-benzo[b]thiophen-3-ylmethyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylicAcid

[0308] Compound 20 was prepared from Intermediate 20B using Method X.HRMS (M−H) calcd C₂₁H₁₆NO₄SClF: 432.0473; found: 432,0485. ¹H NMR showsa mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:2.75(t, J=7), 2.90(dd, J=7, 7), 3.52(t, J=7), 3.69(dd, J=7), 4.59 (s),4.76 (s), 6.26 (s), 6.30 (s), 6.98-7.81(overlapping m).

EXAMPLE 21

[0309] Intermediate 21A:N-(2-Chloro-benzyl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide

[0310] Intermediate 21A was prepared from 4-fluorobenzylamine and5-chloro-3-bromomethyl-benzo[b]thiophene using Method VI. HRMS (M+H)calcd C₁₈H₁₆ClFNOS: 348.0652; found: 348.0619. ¹H NMR and ¹³C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.24(s), 4.41 (s), 4.59 (s), 4.65 (s), 4.79 (s), 6.98-7.33(overlapping m),7.54 (m), 7.74-7.82(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.56,21.81, 41.35, 46.25, 47.94, 49.95, 115.47, 115.64, 115.93, 116.10,120.79, 122.00, 123.77, 124.16, 124.37, 125.18, 125.45, 127.30, 127.95,128.02, 129.98, 130.04, 130.77, 130.92, 131.58, 131.74, 131.77, 133.06,138.33, 138.60, 139.20, 139.35, 161.32, 163.28, 170.93, 171.15.

[0311] Intermediate 21B:3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid Methyl Ester

[0312] Intermediate 21B was prepared from Intermediate 21A using MethodIX. HRMS (M+H) calcd for C₂₁H₁₈NO₄SFCl: 434.0629; found: 434.0626. Anal.calcd for C₂₁H₁₇NO₄SFCl: C, 58.13; H, 3.94; N, 3.22; found: C, 58.42; H,3.95; N, 3.02. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.85 (s), 3.88 (s), 4.49 (s),4.66 (s), 4.69 (s), 4.84 (s), 6.28 (s), 6.34 (s), 7.01-7.81(overlappingm). ¹³C NMR (125 MHz, CDCl₃) δ: 41.50, 45.21, 47.98, 49.17, 53.04,53.06, 93.25, 93.40, 115.73, 115.90, 116.01, 116.18, 120.81, 121.76,123.88, 124.19, 125.35, 125.56, 127.74, 128.35, 128.42, 129.79, 129.99,130.05, 130.43, 130.93, 130.96, 131.03, 131.07, 131.98, 138.22, 138.62,139.09, 139.12, 160.42, 160.45, 161.50, 162.99, 163.07, 163.46, 171.31,171.53.

[0313] Compound 21:3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0314] Compound 21 was prepared from Compound 21B using Method X. HRMS(M−H) calcd for C₂₀H₁₄NO₄SClF: 418.0316; found: 418.0323. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 4.50(s), 4.67 (s), 4.74 (s), 4.85 (s), 6.36 (s), 6.41 (s), 7.01-7.83(overlapping m).

EXAMPLE 22

[0315] Intermediate 22A:N-[2-(4-Fluoro-phenyl)-ethyl]-N-methyl-acetamide

[0316] 2-(4-Fluoro-phenyl)-ethylamine (1.3 g, 9.33 mmol) was dissolvedin 37 mL of CH₂Cl₂. To this was added 37 mL of satd NaHCO₃follwed byacetyl chloride (2.1 mL, 30.9 mmol). The resulting mixture was stirred 6hours. The organic layer was separated, washed with satd NaCl, driedover Na₂SO₄, and the solvent removed under vacuum to yield 280 mg ofN-[2-(fluoro-phenyl)-ethyl]-acetamide.

[0317] N-[2-(fluoro-phenyl)-ethyl]-acetamide (270 mg, 1.5 mmol) wasdissolved in 7.5 mL of toluene to this was added 120 mg of 60% NaH(mineral oil) and MeI (0.12 mL, 1.95 mmol). The resulting mixture wasstirred overnight. The solution was diluted with EtOAc, washed with satdNaCl, dried over Na₂SO₄ and the solvent removed under vacuum. The crudeproduct was purified by flash column chromatography (SiO₂, CH₂Cl₂/EtOH)to yield 230 mg (79% yield) ofN-[2-(4-fluoro-phenyl)-ethyl]-N-methyl-acetamide. HRMS (M+H) calcd forC₁₁H₁₅FNO: 196.1138; found: 196.1137. ¹H NMR shows a mixture of rotamersat room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.85 (s), 2.06 (s), 2.81(m), 2.88 (s), 2.93 (s), 3.48 (m), 3.55 (m), 6.96-7.18 (overlapping m).

[0318] Intermediate 22B:3-{[2-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic AcidMethyl Ester

[0319] Intermediate 22B was prepared from Intermediate 22A using MethodIX. HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found: 282.1135. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 2.87 (m), 2.95 (s), 3.57(t, J=7), 3.63(dd, J=7, 7), 3.87(s), 3.88 (s), 6.05 (s), 6.20 (s), 6.98 (m), 7.15 (m). ¹³C NMR (125 MHz,CDCl₃) δ: 32.90, 34.02, 34.31, 36.18, 49.96, 51.76, 52.91, 52.94, 93.42,93.60, 115.40, 115.57, 115.68, 115.85, 130.17, 130.24, 130.31, 133.25,134.16, 134.19, 159.06, 159.48, 160.74, 160.95, 162.69, 162.90, 163.31,163.37, 170.74.

[0320] Compound 22:3-{[2-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0321] Compound 22 was prepared from Intermediate 22A using Method XI.HRMS (M−H) calcd for C₁₃H₁₃NO₄F: 266.0829; found: 266.0823. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.89 (m), 2.97 (s), 2.98 (s), 3.59(t, J=7), 3.65(dd, J=7, 7),6.13 (s), 6.27 (s), 6.99 (m), 7.14 (m). ¹³C NMR (125 MHz, CDCl₃) δ:32.86, 34.20, 36.26, 50.14, 51.88, 93.33, 115.46, 115.63, 115.75,115.92, 130.17, 130.24, 130.33, 133.032, 133.96, 158.43, 159.11, 165.03,170.72.

EXAMPLE 23

[0322] Intermediate 23A:N-(4-Fluoro-benzyl)-N-(1-phenyl-ethyl)-acetamide

[0323] Intermediate 23A was prepared from 4-fluorobenzylamine and(1-bromo-ethyl)-benzene using Method VI. HRMS (M+H) calcd for C₁₇H₁₉FNO:272.1451; found: 272.1454. ¹H NMR and ¹³C NMR show a mixture of rotamersat room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.42(d, J=7), 1.49(d,J=7), 2.05 (s), 2.29 (s), 3.99(d, J=15), 4.18(d, J=18), 4.37(d, J=18),4.80(d, J=15), 5.17 (m), 6.18 (m), 6.86-7.35 (overlapping m). ¹³C NMR(125 MHz, CDCl₃) δ: 16.96, 19.00, 22.17, 22.52, 114.85, 115.02, 115.42,115.59, 126.72, 127.43, 127.49, 127.55, 127.62, 127.73, 128.52, 128.79,129.10, 129.17, 133.91, 135.03, 140.33, 140.82, 160.69, 162.79, 171.31,171.75.

[0324] Intermediate 23B:3-[(4-Fluoro-benzyl)-(1-phenyl-ethyl)-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0325] Intermediate 23B was prepared from Intermediate 23A using MethodIX. HRMS (M+H) calcd for C₂₀H₂₁NO₄F: 358.1454; found: 358.1456. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.46(d, J=7), 1.55(d, J=7), 3.82 (s), 3.89 (s), 4.12(d,J=16), 4.24(d, J=18), 4.45(d, J=18), 4.77(d, J=16), 5.33(q, J=7), 6.08(s), 6.15(q, J=7), 6.90-7.36 (overlapping m). ¹³C NMR (125 MHz, CDCl₃)δ: 17.00, 18.65, 45.74, 46.45, 51.73, 52.90, 52.98, 55.85, 93.75, 94.71,115.12, 115.30, 115.57, 115.75, 127.02, 127.59, 127.65, 127.71, 127.93,128.14, 128.68, 128.87, 129.00, 129.07, 132.97, 133.00, 133.78, 139.16,139.71, 159.90, 160.11, 161.04, 162.99, 163.15, 163.32, 171.55, 171.86.

[0326] Compound 23:3-[(4-Fluoro-benzyl)-(1-phenyl-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0327] Compound 23 was prepared from Intermediate 23B using Method XI.HRMS (M−H) calcd for C₁₉H₁₇NO₄F: 342.1142; found: 342.1148. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 1.48(d, J=7) 1.54(d, J=7), 4.16(d, J=15), 4.25(d, J=18),4.45(d, J=18), 4.76(d, J=15), 5.32(q, J=7), 6.13 (s), 6.54 (s),6.85-7.36 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 16.98, 18.63,45.82, 46.54, 52.05, 56.07, 93.81, 94.94, 115.20, 115.37, 115.67,115.84, 127.02, 127.60, 127.68, 128.07, 128.27, 128.75, 128.94, 129.04,129.11, 132.61, 132.64, 133.42, 138.84, 139.40, 159.05, 159.37, 161.07,163.03, 164.83, 171.46, 171.76.

EXAMPLE 24

[0328] Intermediate 24A:N-(4-Chloro-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0329] Intermediate 24A was prepared from 4-fluorobenzylamine and4-chlorobenzylchloride using Method VI. HRMS (M+H) calcd forC₁₆H₁₆ClFNO: 292.0905; found: 292.0904. ¹H NMR and ¹³C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.19(s), 2.21 (s), 4.40 (s), 4.53 (s), 6.98-7.35 (overlapping m). ¹³C NMR(125 MHz, CDCl₃) δ: 21.70, 47.31, 50.25, 115.43, 115.60, 115.92, 116.09,127.78, 128.07, 128.13, 128.80, 129.22, 129.71, 130.02, 130.09, 131.81,132.89, 133.36, 133.62, 134.78, 135.72, 161.29, 163.24, 171.02.

[0330] Intermediate 24B:3-[(4-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0331] Intermediate 24B was prepared from Intermediate 24A using MethodIX. HRMS (M+H) calcd for C₁₉H₁₈NO₄ClF: 378.0908; found: 378.0910. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.86 (s), 3.87 (s), 4.46 (s), 4.57 (s), 4.58 (s), 6.29(s), 6.33 (s), 7.00-7.35 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ:47.42, 47.49, 49.41, 49.47, 53.01, 93.26, 115.68, 115.85, 116.02,116.19, 128.09, 128.47, 128.54, 129.01, 129.31, 129.65, 130.04, 130.11,130.99, 131.02, 131.87, 131.89, 133.80, 133.90, 134.04, 134.67, 160.36,161.47, 161.54, 163.05, 163.43, 163.50, 171.41.

[0332] Compound 24:3-[(4-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0333] Compound 24 was prepared from Intermediate 24B using Method X.HRMS (M−H) calcd for C₁₈H₁₄NO₄ClF: 362.0595; found: 362.0606. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 4.45 (s), 4.56 (s), 6.31 (s), 6.35 (s), 6.99-7.35 (overlapping m).

EXAMPLE 25

[0334] Intermediate 25A:N-(2,4-difluoro-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0335] Intermediate 25A was prepared from 4-fluorobenzyl amine and2,4-difluorobenzylbromide using Method VI. HRMS (M+H) calcd forC₁₆H₁₅F₃NO: 294.1106; found: 294.1105. ¹H NMR shows a mixture ofrotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.17(s), 4.39 (s), 4.42 (s), 4.46 (s), 4.51 (s), 6.69-7.30 (overlapping m).

[0336] Intermediate 25B:3-[(2,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid Methyl Ester

[0337] Intermediate 25B was prepared from Intermediate 25A using MethodIX. HRMS (M+H) calcd for C₁₉H₁₇NO₄F₃: 380.1110; found: 380.1100. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 3.87 (s), 3.88 (s), 4.51 (s), 4.52 (s), 4.59 (s), 4.62 (s), 6.33 (s),6.77-7.40 (overlapping m).

[0338] Compound 25:3-[(2,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0339] Compound 25 was prepared from Intermediate 25B using Method X.HRMS (M−H) calcd for C₁₈H₁₃NO₄F₃: 364.0800; found: 364.0800. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 4.47 (s), 4.48 (s), 4.55 (s), 4.58 (s), 6.32 (s), 6.73-7.34(overlapping m).

EXAMPLE 26

[0340] Intermediate 26A:N-(3,5-difluoro-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0341] Intermediate 26A was prepared from 4-fluorobenzylamine and3,4-difluorobenzylamine using Method VI. HRMS (M+H) calcd forC₁₆H₁₄F₃NO: 294.1106; found: 294.1103. ¹H NMR shows a mixture ofrotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.11 (s), 2.13(s), 4.32 (s), 4.35 (s), 4.40 (s), 4.44 (s), 678-7.21 (overlapping m).

[0342] Intermediate 26B:3-[(3,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid Methyl Ester

[0343] Intermediate 26B was prepared from Intermediate 25A using MethodIX. HRMS (M+H) calcd for C₁₉H₁₇NO₄F₃: 380.1110; found: 38.01116. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.88 (s), 4.45 (s), 4.48 (s), 4.55 (s), 4.59 (s), 6.26(s), 6.34 (s), 6.89-7.26 (overlapping m). ¹³C NMR(125 MHz, CDCl₃) δ:47.24, 47.54, 49.07, 49.60, 53.08, 93.06, 93.16, 115.75, 115.87, 115.91,116.08, 116.26, 117.22, 117.36, 117.52, 117.66, 117.99, 118.13, 122.61,124.30, 124.33, 128.46, 128.52, 130.05, 130.12, 130.85, 131.72, 132.44,133.22, 160.45, 160.50, 161.51, 161.57, 163.02, 163.47, 163.54, 171.39,171.43.

[0344] Compound 26:3-[(3,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0345] Compound 26 was prepared from Intermediate 26B using Method X.HRMS (M−H) calcd for C₁₈H₁₃NO₄F₃: 364.0800; found 364.0792. ¹H NMR showsa mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:4.43 (s), 4.46 (s), 4.53 (s), 4.61 (s), 6.27 (s), 6.35 (s), 6.86-7.26(overlapping m).

EXAMPLE 27

[0346] Intermediate 27A: N-tert-Butyl-N-(4-fluoro-benzyl)-acetamide

[0347] Intermediate 27A was prepared from tert-butylamine and4-fluorobenzyl bromide using Method VI. HRMS (M+H) calcd for C₁₃H₁₉FNO:224.1451; found. 224.1456. ¹H NMR (500 MHz, CDCl₃) δ: 1.41 (s, 9), 2.08(s, 3), 4.55 (s, 2), 7.04 (m, 2), 7.17 (m, 2). ¹³C NMR (125 MHz, CDCl₃)δ: 25.06, 28.78, 49.17, 57.71, 115.61, 115.78, 127.04, 127.10, 134.97,134.99,160.97, 162.82, 172.16.

[0348] Intermediate 27B:3-[tert-Butyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0349] Intermediate 27B was prepared from Intermediate 27A using MethodIX. HRMS (M+H) calcd for C₁₆H₂₁NO₄F: 310.1455; found 310.1454. Anal.calcd for C₁₆H₂₀NO₄F: C, 62.12; H, 6.51; N, 4.52; found: C, 62.31; H,6.71; N, 4.52. ¹H NMR (500 MHz, CDCl₃) δ: 1.47(s, 9), 3.2(s, 3), 4.62(s,2), 6.20(s, 1), 7.06(dd, 2, J=9, 9), 7.16(dd, 2, J=5, 9). ¹³C NMR (125MHz, CDCl₃) δ: 28.74, 48.27, 52.86, 58.85, 96.31, 115.81, 115.99,116.61, 127.32, 127.38, 134.00, 159.61, 161.07, 163.02, 163.46, 173.36.

[0350] Compound 27:3-[tert-Butyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0351] Compound 27 was prepared from Intermediate 27B using Method XI.HRMS (M−H) calcd for C₁₅H₁₇NO₄F: 294.1142; found: 294.1144. ¹H NMR (500MHz, CDCl₃) δ: 1.47(s, 9), 4.62(s, 2), 6.12(br s, 1), 7.04(m, 2),7.14(m, 2). ¹³C NMR (125 MHz, CDCl₃) δ: 28.68, 48.34, 59.15, 96.45,115.86, 116.03, 127.28, 127.35, 133.64, 159.01, 161.09, 163.05, 165.61,173.28.

EXAMPLE 28

[0352] Intermediate 28A:N-(3-Chloro-benzyl)-N-4-fluoro-benzyl)-acetamide

[0353] Intermediate 28A was prepared from 4-fluorobenzylamine and3-chlorobenzylchloride using Method VI. HRMS (M+H) calcd forC₁₆H₁₆ClFNO: 292.0905; found: 292.0902. ¹H NMR and ¹³ C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.19(s), 2.23 (s), 4.41 (s), 4.55(s), 6.97-7.38 (overlapping m). ¹³C NMR(125 MHz, CDCl₃) δ: 21.67, 47.50, 50.37, 115.44, 115.61, 115.92, 116.09,124.47, 126.41, 126.52, 127.72, 128.00, 128.07, 128.14, 128.22, 129.92,130.04, 130.11, 130.34, 131.77, 131.80, 132.88, 132.90, 134.56, 135.13,138.49, 139.29, 161.31, 163.26, 171.05.

[0354] Intermediate 28B:3-[(3-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0355] Intermediate 28B was prepared from Intermediate 28A using MethodIX. HRMS (M+H) calcd for C₁₉H₁₈NO₄FCl: 378.0908; found: 378.0903. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.87 (s), 3.88 (s), 4.47 (s), 4.48 (s), 4.59 (s), 4.60(s), 6.28 (s), 6.35 (s), 7.01-7.31 (overlapping m). ¹³C NMR (125 MHz,CDCl₃) δ: 47.57, 47.59, 49.49, 49.60, 53.05, 93.23, 93.24, 115.70,115.87, 116.04, 116.21, 124.78, 126.33, 126.82, 128.12, 128.20, 128.38,128.49, 128.55, 130.07, 130.14, 130.44, 130.94, 130.96, 131.83, 131.85,134.77, 135.16, 137.52, 138.22, 160.38, 160.39, 161.49, 161.55, 163.05,163.08, 163.45, 163.51, 171.44.

[0356] Compound 28;3-[(3-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0357] Compound 28 was prepared from Intermediate 28B using Method X.HRMS (M+H) calcd for C₁₈H₁₆NO₄ClF: 364.0752; found: 364.0758. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 4.48 (s), 4.49 (s), 4.60 (s), 4.61 (s), 6.35 (s), 6.42 (s),7.02-7.34 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 47.49, 49.57,49.70, 93.57, 115.76, 115.94, 116.11, 116.28, 124.77, 126.35, 126.80,128.23, 128.49, 128.57, 130.11, 130.18, 130.49, 134.81, 135.21, 137.23,137.94, 159.45, 164.76, 171.34.

EXAMPLE 29

[0358] Intermediate 29A: N-(4-Fluoro-benzyl)-N-isopropyl-acetamide

[0359] Intermediate 29A was prepared from 4-fluorobenzylbromide andisopropylamine using Method VI. HRMS (M+H) calcd for C₁₂H₁₇FNO:210.1294; found: 210.1293. ¹H NMR and ¹³C NMR show a mixture of rotamersat room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.08 (d, J=7), 1.13(d,J=7), 2.00 (s), 2.23 (s), 4.12(p, J=7), 4.42 (s), 4.49 (s), 4.86(p,J=7), 6.93 (m), 7.05 (m), 7.19 (m). ¹³ C NMR (125 MHz, CDCl₃) δ: 20.33,21.51, 22.03, 22.59, 43.05, 45.51, 46.31, 49.79, 114.99, 115.16, 115.57,115.74, 127.33, 128.64, 134.17, 135.42, 160.71, 160.93, 162.65, 162.89,170.70, 171.36.

[0360] Intermediate 29B:3-[(4-Fluoro-benzyl)-isopropyl-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0361] Intermediate 29B was prepared from Intermediate 29A using MethodIX. HRMS (M+H) calcd for C₁₅H₁₉NO₄F: 296.1298; found: 296.1299. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.14(d, J=7), 1.19(d, J=7), 3.81 (s), 3.90 (s),4.28(heptet, J=7), 4.49 (s), 4.59 (s), 4.84(heptet, J=7), 6.03 (s), 6.40(s), 6.97-7.22 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 20.23,21.51, 43.51, 45.55, 46.04, 49.13, 52.88, 52.99, 93.54, 94.71, 115.32,115.49, 115.75, 115.92, 127.57, 127.64, 128.50, 128.57, 133.14, 134.11,159.74, 159.95, 160.90, 161.13, 162.85, 163.09, 163.25, 163.46, 171.08,171.65.

[0362] Compound 29:3-[(4-Fluoro-benzyl)-isopropyl-carbamoyl]-2-hydroxy-acrylic Acid

[0363] Compound 29 was prepared from Intermediate 29B using Method XI.HRMS (M−H) calcd C₁₄H₁₅NO₄F: 280.9851; found: 280.988. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:1.16(d, J=7), 1.20(d, J=7), 4.28(heptet, J=7), 4.51 (s), 4.61 (s),4.82(heptet, J=7), 6.10 (s), 6.47 (s), 7.03 (m), 7.15 (m), 7.21 (m).

EXAMPLE 30

[0364] Intermediate 30A: N-Methyl-N-(4-methyl-benzyl)-acetamide

[0365] Intermediate 30A was prepared from N-(4-methyl-benzyl)-acetamideand methyl iodide using Method VII. HRMS (M+H) calcd for C₁₁H₁₆NO:178.1232; found: 178.1230. ¹H NMR and ¹³C NMR show a mixture of rotamersat room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.15 (s), 2.33(s), 2.35 (s), 2.90 (s), 2.92 (s), 4.48 (s), 4.54 (s), 7.05-7.18(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.07, 21.12, 21.46, 21.68,33.68, 35.44, 50.33, 54.05, 126.32, 128.10, 129.27, 129.63, 133.44,134.30, 137.04, 137.41, 170.74, 171.08.

[0366] Intermediate 30B:2-Hydroxy-3-[methyl-(4-methyl-benzyl)-carbamoyl]-acrylic Acid MethylEster

[0367] Intermediate 30B was prepared from Intermediate 30A using MethodIX. HRMS (M+H) calcd for C₁₄H₁₈NO₄: 264.1236; found: 264.1243. Analcalcd for C₁₄H₁₇NO₄: C, 63.96; H, 6.50; N, 5.32; found: C, 63.57; H,6.50; N, 5.28. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.34 (s), 2.99 (s), 3.86 (s),3.89 (s), 4.54 (s), 4.61 (s), 6.29 (s), 6.34 (s), 7.06-7.18 (overlappingm). ¹³C NMR (125 MHz, CDCl₃) δ: 21.12, 33.47, 34.75, 50.37, 52.91,53.09, 93.56, 93.66, 126.65, 128.00, 129.48, 129.71, 132.51, 133.16,137.53, 137.86, 159.59, 163.35, 170.87, 171.19.

[0368] Compound 30:2-Hydroxy-3-[methyl-(4-methyl-benzyl)-carbamoyl]-acrylic Acid

[0369] Compound 30 was prepared from Intermediate 30B using Method XI.HRMS (M−H) calcd for C₁₃H₁₄NO₄: 248.0923; found: 248.0926. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.34 (s), 3.01 (s), 3.02 (s), 4. 55 (s), 4.62 (s), 6.36 (s),6.42 (s), 7.06-7.18 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.13,33.72, 34.85, 50.58, 53.23, 93.67, 93.74, 126.69, 128.03, 129.54,129.77, 132.20, 132.83, 137.68, 138.00, 158.90, 159.111, 165.36, 170.80,171.08.

EXAMPLE 31

[0370] Intermediate 31A: N-(4-Methoxy-benzyl)-N-methyl-acetamide

[0371] 4-Methoxybenzyl amine (3.8 grams, 27.8 mmol) was dissolved in 100mL of methylene chloride, to this was added 100 mL of satd NaHCO₃ (aq.)followed by acetyl chloride (3.0 mL, 41.7 mmol). After stirring 1 h, anadditional 41.7 mmol of acetyl chloride was added and the resultingmixture stirred overnight. The organic layer was separated, washed withsatd NaCl (aq.), dried over Na₂SO₄, filtered and solvent removed undervacuum. Crude N-(4-methoxybenzyl)-acetamide was purified by flash columnchromatography (SiO₂, 2% EtOH in methylene chloride) 1.75 grams (35%yield) as a white solid.

[0372] Sodium hydride (60% in mineral oil) (1.11 grams, 27.4 mmol) wasmeasured into a round bottom flask and triturated with hexanes. To thiswas added pure N-(4-methoxybenzyl)-acetamide (1.23 grams, 6.9 mmol)followed by iodomethane (1.95 grams, 13.7 mmol)and the resulting mixturestirred overnight. The reaction was filtered and the solvent removedunder vacuum. The crude product was purified by flash columnchromatography (SiO₂, 2% EtOH in methylene chloride) to yield 1.2 gramsof a colorless oil. HRMS (M+H) calcd for C₁₁H₁₆NO₂: 194.1181; found:194.1177. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.15 (s), 2.89 (s),2.90 (s), 3.78 (s), 3.80 (s), 4.45 (s), 4.50 (s), 6.86 (m), 7.08 (d,J=9), 7.17 (d, J=9). ¹³C NMR (125 MHz, CDCl₃) δ: 21.50, 21.91, 33.49,35.33, 49.95, 53.72, 55.28, 113.95, 114.32, 127.66, 128.46, 129.44,129.52, 158.95, 159.13, 170.63, 170.91.

[0373] Intermediate 31B:2-Hydroxy-3-[(4-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid MethylEster

[0374] Intermediate 31B was prepared from Intermediate 31A using MethodIX. HRMS (M+H) calcd for C₁₄H₁₈NO₅: 280.1185; found: 280.1188. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 2.98 (s), 3.80 (s), 3.89 (s), 3.90 (s), 4.52 (s), 4.58(s), 6.28 (s), 6.36 (s), 6.88 (m), 7.10 (d, J=8), 7.18 (d, J=8). ¹³C NMR(125 MHz, CDCl₃) δ: 33.30, 34.62, 50.03, 52.77, 52.91, 55.32, 93.53,93.69, 114.18, 114.42, 127.49, 128.05, 128.28, 129.44, 159.27, 159.42,159.57, 163.35, 170.80, 171.08.

[0375] Compound 31:2-Hydroxy-3-[(4-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid

[0376] Compound 31 was prepared from Intermediate 31B using Method XI.HRMS (M−H) calcd for C₁₃H₁₄NO₅: 264.0872; found: 264.0874. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.99 (s), 3.00 (s), 3.80 (s), 4.52 (s) 4.59 (s), 6.34 (s),6.43 (s), 6.89 (m), 7.10 (d, J=8), 7.19 (d, J=8). ¹³C NMR (125 MHz,CDCl₃) δ: 33.52, 34.71, 50.25, 52.90, 55.35, 93.45, 114.25, 114.38,114.49, 127.19, 127.95, 128.12, 129.48, 129.70, 159.03, 159.21, 159.32,159.48, 164.89, 170.77, 171.01.

EXAMPLE 32

[0377] Intermediate 32A: N-Ethyl-N-(4-fluoro-benzyl)-acetamide

[0378] Intermediate 32A was prepared from 4-fluorobenzylbromide andN-ethylacetamide using Method VII. HRMS (M+H) calcd C₁₁H₁₅FNO: 196.1138;found: 196.1137. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.11 (m), 2.10 (s), 2.17 (s),3.25 (q, J=7), 3.40 (q, J=7), 4.48 (s), 4.54 (s), 6.97-7.26 (overlappingm). ¹³C NMR (125 MHz, CDCl₃) δ: 12.67, 13.61, 21.29, 21.79, 40.70,42.46, 47.12, 50.89, 115.28, 115.44, 115.74, 115.91, 127.87, 127.94,129.65, 129.71, 132.64, 132.67, 133.66, 133.69, 161.15, 163.10, 170.43,170.61.

[0379] Intermediate 32B:3-[Ethyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0380] Intermediate 32B was prepared from Intermediate 32A using MethodIX. HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found 282.1134. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.18 (overlapping m), 3.35 (q, J=7), 3.46 (q, J=7), 3.85(s), 3.89 (s), 4.54 (s), 4.60 (s), 6.22 (s), 6.26 (s), 6.99-7.25(overlapping m) ¹³C NMR (125 MHz, CDCl₃) δ: 12.62, 14.00, 41.06, 42.16,47.70, 50.10, 52.92, 52.96, 93.55, 93.59, 115.55, 115.72, 115.88,116.05, 128.24, 128.31, 129.67, 129.73, 132.63, 159.80, 161.35, 163.31,163.34, 170.60, 170.98.

[0381] Compound 32:3-[Ethyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0382] Compound 32 was prepared from Intermediate 32B using Method XI.HRMS (M−H) calcd for C₁₃H₁₃NO₄: 266.0829; found: 266.0829, 1 ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 1.19 (overlapping m), 3.36 (q, J=7), 3.47 (q, J=7), 4.55 (s),4.61 (s), 6.30 (s), 6.33 (s), 7.03 (m), 7.16 (m), 7.25 (m). ¹³C NMR (125MHz, CDCl₃) δ: 12.58, 13.96, 41.32, 42.31, 47.91, 50.22, 93.46, 115.63,115.80, 115.96, 116.13, 128.29, 128.35, 129.71, 129.78, 131.45, 132.28,132.31, 159.331, 159.39, 163.37, 164.90, 170.58, 170.97.

EXAMPLE 33

[0383] Intermediate 33A: N-(3-Methoxy-benzyl)-N-methyl-acetamide

[0384] Intermediate 33A was prepared from N-methylacetamide and3-methoxybenzylbromide using Method VII. HRMS (M+H) calcd for C₁₁H₁₆NO₂:194.1181; found: 194.1180. ¹H NMR and ¹³C NMR show a mixture of rotamersat room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.14 (s), 2.91(s), 2.93 (s), 3.78 (s), 3.79 (s), 4.48 (s), 4.55 (s), 6.69-6.83(overlapping m), 7.21-7.29 (overlapping m).

[0385] Intermediate 33B:2-Hydroxy-3-[(3-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid MethylEster

[0386] Intermediate 33B was prepared from Intermediate 33A using MethodIX. HRMS (M+H) calcd for C₁₄H₁₈NO₅: 280.1185; found 280.1183. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.01 (s), 3.79 (s), 3.85 (s), 3.89 (s), 4.55 (s), 4.62 (s),6.30 (s), 6.31 (s), 6.70-6.85 (overlapping m), 7.29 (m). ¹³C NMR (125MHz, CDCl₃) δ: 33.62, 34.89, 50.58, 52.93, 53.22, 55.27, 93.46, 93.59,112.57, 113.02, 113.67, 118.81, 120.19, 129.84, 130.17, 137.24, 137.81,159.65, 160.01, 160.19, 163.32, 170.95, 171.28.

[0387] Compound 33:2-Hydroxy-3-[(3-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid

[0388] Compound 33 was prepared from Intermediate 33B using Method XI.HRMS (M−H) calcd for C₁₃H₁₄NO₅: 264.0872; found: 264.0868. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.02 (s), 3.03 (s), 3.80 (s), 4.56 (s), 4.63 (s) 6.36 (s),6.38 (s), 6.70-6.85 (overlapping m), 7.26 (m). ¹³ C NMR (125 MHz, CDCl₃)δ: 33.82, 34.98, 50.75, 53.33, 55.30, 93.55, 112.62, 113.08, 113.14,113.36, 113.73, 114.76, 118.86, 120.22, 122.03, 129.90, 130.28, 136.97,137.54, 159.21, 159.39, 159.99, 160.06, 165.18, 170.96, 171.25.

EXAMPLE 34

[0389] Intermediate 34A: N-Biphenyl-3-ylmethyl-N-methyl-acetamide

[0390] C-Biphenyl-3-yl-methylamine (700 mg, 3.8 mmol) was dissolved in38 mL of CH₂Cl₂. To this was added 38 mL of satd NaHCO₃ (aq) followed byacetyl chloride (1.41 mL 19.8 mmol). The resulting mixture was stirred45 min. The organic layer was separated, washed with satd NaCl, driedover Na₂SO₄, filtered and solvent removed under vacuum to yield 1.1grams of N-biphenyl-3-ylmethyl-acetamide.

[0391] N-biphenyl-3-ylmethyl-acetamide (860 mg, 3.8 mmol) was dissolvedin 10 mL of toluene. To this was added 611 mg of 60% NaH (mineral oil)and MeI (0.48 mL, 7.6 mmol). The resulting mixture was stirred overnightthen filtered. The solvent was removed under vacuum to yield 980 mg(108% yield) of N-biphenyl-3-ylmethyl-N-methyl-acetamide. HRMS ((M+H)calcd for C₁₆H₁₈N): 240.1389; found: 240.1398. ¹H NMR and ¹³C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.17(s), 2.19 (s), 2.96 (s), 2.99 (s), 4.60 (s), 4.66 (s), 7.15-7.60(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.55, 21.91, 33.84, 35.61,50.66, 54.33, 125.05, 125.16, 126.25, 126.55, 126.85, 127.00, 127.20,127.23, 127.42, 127.65, 128.79, 128.90, 129.06, 129.45, 137.19, 137.95,140.65, 140.95, 141.64, 142.12, 170.79, 171.08.

[0392] Intermediate 34B:3-(Biphenyl-3-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid MethylEster

[0393] Intermediate 34B was prepared from Intermediate 34A using MethodIX. HRMS (M+H) calcd for C₁₉H₂₀NO₄: 326.1392; found: 326.1398. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.04 (s), 3.06 (s), 3.87 (s), 3.90 (s), 4.65 (s), 4.73(s), 6.33 (s), 6.38 (s), 7.16-7.59 (overlapping m). ¹³C NMR (125 MHz,CDCl₃) δ: 33.68, 34.95, 50.69, 52.95, 53.34, 93.48, 93.65, 125.40,125.44, 126.66, 126.76, 126.87, 126.93, 127.20, 127.57, 127.72, 128.88,128.94, 129.31, 129.58, 136.22, 136.82, 140.53, 140.73, 141.88, 142.17,159.69, 163.32, 171.01, 171.33.

[0394] Compound 34:3-(Biphenyl-3-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0395] Compound 34 was prepared from Intermediate 34B using Method X.HRMS (M+H) calcd for C₁₈H₁₈NO₄: 312.1236; found: 312.1250. ¹H NMR showsa mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:3.05 (s), 3.08 (s), 4.65 (s), 4.73 (s), 6.39 (s), 6.46 (s), 7.15-7.59(overlapping m).

EXAMPLE 35

[0396] Intermediate 35A:N-(2,4-Dimethoxy-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0397] Intermediate 35A was prepared from(2,4-dimethoxy-benzyl)-(4-fluoro-benzyl)-amine using Method IV. HRMS(M+H) calcd for C₁₈H₂₁FNO₃: 318.1506; found: rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.22 (s), 3.71 (s),3.77 (s), 3.79 (s), 3.81 (s), 4.34 (s), 4.46 (s), 4.51 (s), 4.55 (s),6.45 (m), 6.92-7.22 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.61,21.82, 42.89, 46.56, 47.10, 50.86, 55.19, 55.46, 98.30, 98.68, 103.87,104.25, 115.16, 115.33, 115.56, 115.73, 116.50, 117.85, 127.83, 127.90,128.29, 129.79, 129.85, 131.00, 132.97, 133.53, 133.55, 158.35, 158.58,160.34, 160.66, 161.09, 163.03, 171.11, 171.46.

[0398] Intermediate 35B:3-[(2,4-Dimethoxy-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid Methyl Ester

[0399] Intermediate 35B was prepared from Intermediate 35A using MethodIX. HRMS (M+H) calcd for C₂₁H₂₃NO₆F: 404.1510; found: 404.1514. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.73 (s), 3.78 (s), 3.80 (s), 3.81 (s), 3.85 (s), 3.87(s), 4.42 (s), 4.53 (s), 4.58 (s), 4.60 (s), 6.27 (s), 6.42 (s), 6.45(s), 6.94-7.23 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 43.10,45.55, 47.29, 49.88, 52.91, 55.20, 55.26, 55.46, 93.77, 94.39, 98.43,98.68, 104.09, 104.36, 115.44, 115.61, 115.67, 115.76, 115.84, 116.66,128.26, 128.32, 128.86, 129.80, 129.86, 131.02, 132.05, 132.50, 132.52,158.37, 158.60, 159.40, 159.83, 160.70, 160.94, 161.28, 163.24, 163.31,163.41, 171.36, 171.46.

[0400] Compound 35:3-[(2,4-Dimethoxy-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0401] Compound 35 was prepared from Intermediate 35B using Method XI.HRMS (M+H) calcd for C₂₀H₂₁NO₆F: 390.1353; found: 390.1362.

EXAMPLE 36

[0402] Intermediate 36A: N-(4-Benzyloxy-benzyl)-N-methyl-acetamide

[0403] Intermediate 36A was prepared from 4-benzyloxy-benzylchlorideusing Method VI. HRMS (M+H) calcd for C₁₇H₂₀NO₂: 270.1494; found:270.1491. ¹H NMR and ¹3C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.16 (s), 2.90 (s),2.92 (s), 4.46 (s), 4.52 (s), 5.05 (s), 5.07 (s), 6.92-7.44 (overlappingm). ¹³C NMR (125 MHz, CDCl₃) δ: 21.52, 21.93, 33.52, 35.37, 49.98,53.73, 70.06, 70.13, 114.92, 115.29, 127.49, 127.53, 127.62, 127.68,127.99, 128.07, 128.61, 128.65, 128.67, 128.80, 129.46, 129.85, 136.84,137.00, 158.19, 158.35, 170.62, 170.89.

[0404] Compound 36:3-[(4-Benzyloxy-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0405] Compound 36 was prepared from Intermediate 36A using Method XII.HRMS (M+H) calcd for C₁₉H₂₀NO₅: 342.1342; found: 342.1352. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) 2.90 (s), 4.43 (s), 4.50 (s) 4.97 (s), 6.21 (s), 6.29 (s),6.87-7.35 (overlapping m). ¹³ C NMR (125 MHz, CDCl₃) δ: 33.42, 34.62,49.91, 52.66, 69.99, 93.20, 93.34, 115.03, 115.25, 127.45, 127.89,127.98, 128.08, 128.57, 128.66, 129.34, 136.73, 136.82, 158.32, 158.47,160.24, 164.44, 170.99, 171.24.

EXAMPLE 37

[0406] Intermediate 37A: N-Methyl-N-(3-trifluoromethyl-benzyl)-acetamide

[0407] Intermediate 37A was prepared from 3-trifluorobenzyl bromideusing Method VII. HRMS (M+H) calcd for C₁₁H₁₃F₃NO: 232.0949; found:232.0945. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.17 (s), 2.94 (s),4.58 (s), 4.62 (s), 7.37-7.55 (overlapping m). ¹³C NMR (125 MHz, CDCl₃)δ: 21.44, 21.77, 33.76, 35.71, 122.97. 123.12, 123.15, 124.23, 124.26,124.29, 124.56, 124.59, 124.62, 124.64, 125.13, 129.15, 129.53, 129.58,130.55, 130.81, 131.07, 131.34, 131.59, 137.78, 138.48, 170.91, 170.95.

[0408] Intermediate 37B:2-Hydroxy-3-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-acrylic AcidMethyl Ester

[0409] Intermediate 37B was prepared from Intermediate 37A using MethodIX. HRMS (M+H) calcd for C₁₄H₁₅NO₄F₃: 318.0953; found: 318.0948. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.02 (s), 3.03 (s), 3.84 (s), 3.88 (s), 4.64 (s), 4.70(s), 6.27 (s), 6.31 (s), 7.36-7.59 (overlapping m). ¹³C NMR (125 MHz,CDCl₃) δ: 33.65, 35.05, 50.34, 52.87, 52.97, 93.04, 93.42, 122.86,123.46, 123.49, 124.55, 124.58, 124.61, 124.64, 124.68, 124.71, 125.02,129.41, 129.74, 129.81, 130.78, 131.03, 131.25, 131.36, 131.55, 131.62,136.79, 137.39, 159.82, 159.93, 163.12, 163.17, 171.14, 171.35.

[0410] Compound 37:2-Hydroxy-3-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-acrylic Acid

[0411] Compound 37 was prepared from Intermediate 37B using Method X.Anal Calcd for C₁₃H₁₂NO₄F₃: C, 51.49; H, 3.98; N, 4.62; found: C, 51.72;H, 3.76; N, 4.39. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.05 (s), 4.66 (s), 4.72 (s),6.36 (s), 6.39 (s), 7.36-7.61 (overlapping m). ¹³C NMR (125 MHz, CDCl₃)δ: 33.85, 35.14, 50.53, 52.98, 93.32, 93.72, 122.83, 123.51, 124.65,124.68, 124.82, 124.85, 124.99, 125.14, 129.48, 129.81, 131.13, 131.27,131.39, 136.44, 137.07, 159.04, 159.17, 165.05, 165.13, 171.04, 171.26.

EXAMPLE 38

[0412] Intermediate 38A: N-(2-Fluoro-benzyl)-N-methyl-acetamide

[0413] Intermediate 38A was prepared from 2-fluoro-benzyl bromide usingMethod VII. HRMS (M+H) calcd for C₁₀H₁₃FNO: 182.0981; found: 182.0982.¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.14 (s), 2.16 (s), 2.94 (s), 2.97 (s), 4.56 (s), 4.64 (s),7.01-7.31 (overlapping m).

[0414] Intermediate 38B:3-[(2-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0415] Intermediate 38B was prepared from Intermediate 38A using MethodIX. HRMS (M+H) calcd for C₁₃H₁₅NO₄F: 268.0985; found: 268.0992. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.02 (s), 3.05 (s), 3.84 (s), 3.87 (s), 4.62 (s), 4.70(s), 6.28 (s), 6.32 (s), 7.03-7.30 (overlapping m). ¹³C NMR (125 MHz,CDCl₃) δ: 33.55, 35.21, 44.27, 44.30, 47.24, 47.28, 93.40, 93.57,115.40, 115.57, 115.70, 115.87, 122.66, 122.77, 123.15, 123.27, 124.53,124.55, 124.65, 124.68, 128.26, 128.29, 129.53, 129.60, 129.84, 129.91,130.34, 130.37, 159.59, 159.65, 160.07, 161.61, 162.03, 163.24, 171.11,171.34.

[0416] Compound 38:3-[(2-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid:

[0417] Compound 38 was prepared from Intermediate 38B using Method XI.HRMS (M+H) calcd for C₁₂H₁₃NO₄F: 254.0829; found: 254.0833. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.04 (s), 3.07 (s), 4.64 (s), 4.72 (s), 6.36 (s), 6.41 (s),7.05-7.20 (overlapping m), 7.31 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.75,35.29, 44.84, 44.51, 47.43, 47.46, 93.81, 93.85, 115.46, 115.64, 115.78,115.95, 122.39, 122.51, 122.90, 123.02, 124.58, 124.60, 124.71, 124.73,128.40, 128.43, 129.67, 129.74, 130.00, 130.06, 130.40, 130.43, 158.92,159.03, 159.68, 160.08, 161.64, 162.04, 165.48, 171.03, 171.23

EXAMPLE 39

[0418] Intermediate 39A: N-Biphenyl-2-ylmethyl-N-methyl-acetamide

[0419] Intermediate 39A was prepared from C-Biphenyl-2-yl-methylamineusing the same Method as Intermediate 34A. LCMS (M+H) calcd forC₁₆H₁₈NO: 240.1; found: 240.1

[0420] Intermediate 39B:3-(Biphenyl-2-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid MethylEster

[0421] Intermediate 39B was prepared from Intermediate 39A using MethodIX. HRMS (M+H) calcd for C₁₉H₂₀NO₄: 326.1392; found: 326.1396. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 2.80 (s), 2.90 (s), 3.86 (s), 3.89 (s), 3.92 (s), 4.51(s), 4.68 (s), 6.12 (s), 6.21 (s), 7.18-7.46 (overlapping m). ¹³ C NMR(125 MHz, CDCl₃) δ: 33.53, 34.76, 48.13, 51.34, 52.88, 52.94, 53.67,93.48, 93.52, 126.43, 127.41, 127.47, 127.55, 127.62, 127.81, 127.96,128.13, 128.39., 128.62, 128.92, 129.05, 130.30, 130.49, 132.90, 133.29,140.09, 140.44, 141.70, 142.05, 159.32, 159.49, 163.28, 163.36, 170.96,171.25.

[0422] Compound 39:3-(Biphenyl-2-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0423] Compound 39 was prepared from Intermediate 39B using Method XI.HRMS (M−H) calcd for C₁₈H₁₆NO₄: 310.1079; found: 310.1074. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 2.80 (s), 2.91 (s), 4.52 (s), 4.69 (s), 6.16 (s), 6.27 (s),7.18-7.45 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.70, 34.82,48.33, 51.50, 93.51, 93.79, 126.58, 127.45, 127.61, 127.66, 127.94,128.01, 128.15, 128.43, 128.68, 128.90, 129.03, 130.36, 130.56, 132.63,133.02, 140.01, 140.38, 141.80, 142.09, 158.63, 159.02, 165.27, 170.88,171.11.

EXAMPLE 40

[0424] Intermediate 40A: N-(3-Fluoro-benzyl)-N-methyl-acetamide

[0425] Intermediate 40A was prepared from 3-fluorobenzoyl chloride usingMethods II and IV. HRMS (M+H) calcd for C₁₀H₁₃FNO: 182.0981; found:182.0982. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.07 (s), 2.10 (s), 2.87 (s),2.88 (s), 4.45 (s), 4.51 (s), 6.80-7.28 (overlapping m). ¹³C NMR (125MHz, CDCl₃) δ: 21.68, 22.06, 34.08, 35.95, 50.49, 50.50, 54.08, 54.09,113.47, 113.64, 114.45, 114.62, 114.81, 114.91, 114.98, 115.08, 122.08,122.10, 123.76, 123.79, 130.34, 130.41, 130.85, 130.91, 139.60, 139.66,140.26, 140.32, 162.33, 162.57, 164.29, 164.54, 171.08, 171.24.

[0426] Intermediate 40B:3-[(3-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0427] Intermediate 40A was prepared from Intermediate 40A using MethodIX. HRMS (M+H) calcd for C₁₃H₁₅NO₄F: 268.0985; found: 268.0987. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.03 (s), 3.86 (s), 3.90 (s), 4.58 (s), 4.65 (s), 6.27(s), 6.31 (s), 6.99 (m), 7.31 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.68,35.02, 50.26, 52.82, 52.99, 93.19, 93.46, 113.54, 113.72, 114.68,114.85, 115.00, 115.17, 122.14, 123.44, 123.46, 130.36, 130.42, 130.72,130.79, 138.80, 138.85, 159.78, 162.10, 163.24, 164.07, 171.05, 171.30.

[0428] Compound 40:3-[(3-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0429] Compound 40 was prepared from Intermediate 40B using Method XI.HRMS (M−H) calcd for C₁₂H₁₁NO₄F: 252.0672.; found: 252.0668. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.04 (s), 4.59 (s), 4.65 (s), 6.35 (s), 6.38 (s), 6.87-7.03(overlapping m), 7.33 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.90, 35.11,50.43, 52.94, 93.61, 93.84, 113.55, 113.73, 114.73, 114.78, 114.90,114.95, 115.10, 115.26, 122.19, 123.49, 130.42, 130.48, 130.80, 130.68,137.99, 138.50, 138.56, 159.06, 162.09, 162.24, 164.06, 165.46, 170.94,171.20.

EXAMPLE 41

[0430] Intermediate 41A:N-(4-Fluoro-naphthalen-1-ylmethyl)-N-methyl-acetamide

[0431] Intermediate 41A was prepared from4-fluoro-naphthalene-1-carboxylic acid using Methods II and IV. HRMS(M+H) calcd for C₁₄H₁₅FNO: 232.1138; found: 232.1135. ¹H NMR and ¹³C NMRshow a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 2.13 (s), 2.17 (s), 2.82 (s), 3.04 (s), 4.94 (s), 5.01 (s), 7.06-8.19(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.29, 22.07, 34.26, 34.80,47.99, 51.78, 108.43, 108.59, 108.90, 109.06, 121.10, 121.15, 121.67,121.71, 122.04, 122.06, 122.49, 122.56, 124.04, 124.13, 124.15, 126.32,126.33, 126.44, 126.97, 127.03, 127.14, 127.17, 127.53, 127.57, 128.65,128.68, 131.88, 132.96, 133.00, 157.52, 157.81, 159.53, 159.81, 170.55,171.58.

[0432] Intermediate 41B:3-[(4-Fluoro-naphthalen-1-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylicAcid Methyl Ester

[0433] Intermediate 41B was prepared from Intermediate 41A using MethodIX. HRMS (M+H) calcd for C₁₇H₁₇NO₄F, 318.1142; found: 318.1144. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 2.93 (s), 3.09 (s), 3.81 (s), 3.90 (s), 5.02 (s), 5.09(s), 6.22 (s), 6.30 (s) 7.11 (m), 7.28 (m), 7.6 (m), 7.85 (d, J=8), 8.05(m), 8.16 (m), 8.19 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.90, 34.09,47.95, 50.85, 52.93, 52.99, 93.31, 93.76, 108.56, 108.72, 108.92,109.08, 121.32, 121.36, 121.74, 121.78, 122.10, 123.33, 123.40, 123.60,123.62, 124.11, 124.43, 126.51, 126.57, 126.99, 127.06, 127.37, 127.41,127.76, 127.80, 132.80, 132.84, 158.02, 159.75, 159.88, 160.03, 163.19,163.29, 170.73, 171.76.

[0434] Compound 41:3-[(4-Fluoro-naphthalen-1-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylicAcid

[0435] Compound 41 was prepared from Intermediate 41B using Method XI.HRMS (M−H) calcd for C₁₆H₁₄NO₄F: 302.0829; found: 302.0821. ¹H NMR showsa mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:3.00 (s), 3.04 (s), 5.08 (s), 5.20 (s), 6.17 (s), 6.31 (s), 7.11 (m),7.33 (m), 7.40 (m), 7.69 (m), 8.12 (m).

EXAMPLE 42

[0436] Intermediate 42A:N-(4-Fluoro-benzyl)-N-(2-methoxy-ethyl)-acetamide

[0437] Intermediate 42A was prepared from 4-fluorobenzylamine and1-bromo-2-methoxy ethane using Method VI. HRMS (M+H) calcd forC₁₂H₁₇FNO₂: 226.1243; found: 226.1244 . ¹H NMR and ¹³C NMR show amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.17(s), 2.24 (s), 3.30 (s), 3.31 (s), 3.43 (s), 3.55 (s), 4.63 (s), 4.64(s), 6.98-7.23 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.25,21.32, 46.08, 47.87, 48.46, 52.91, 58.85, 59.10, 70.25, 71.05, 115.40,115.57, 115.82, 115.99, 127.92, 127.98, 129.73, 129.80, 132.09, 132.12,132.96, 132.98, 158.91, 159.23, 161.26, 161.28, 163.22, 163.24, 172.34,172.61.

[0438] Intermediate 42B:3-[(4-Fluoro-benzyl)-(2-methoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0439] Intermediate 42B was prepared from Intermediate 42A using MethodIX. HRMS (M+H) calcd for C₁₅H₁₉NO₅F: 312.1247; found: 312.1256. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.32 (s), 3.58 (m), 3.85 (s), 3.89 (s), 4.67 (s), 4.69(s), 6.25 (s), 6.31 (s), 7.03 (m), 7.15 (m), 7.24 (m). ¹³C NMR (125 MHz,CDCl₃) δ: 45.84, 46.90, 48.87, 51.79, 52.97, 58.95, 59.16, 70.81, 70.89,93.64, 93.89, 115.53, 115.70, 115.82, 115.99, 128.27, 128.33, 129.70,129.77, 131.84, 131.86, 132.54, 132.56, 159.54, 159.83, 161.34, 161.38,163.21, 163.29, 163.34, 171.17, 171.43.

[0440] Compound 42:3-[(4-Fluoro-benzyl)-(2-methoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0441] Compound 42 was prepared from Intermediate 42B using Method XI.HRMS (M−H) calcd for C₁₄H₁₅NO₅F: 296.0934; found: 296.0940. ¹H NMR showsa mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:3.22 (s), 3.45 (m), 3.57 (m), 4.64 (s), 4.73 (s), 6.17 (s), 6.32 (s),7.15-7.33 (overlapping m).

EXAMPLE 43

[0442] Intermediate 43A:N-(4-Fluoro-benzyl)-N-(3-phenyl-propyl)-acetamide

[0443] 4-Fluorobenzylamine (11.4 g, 91 mmol) was dissolved in 910 mL ofCH₂Cl₂. To this was added 910 mL of satd NaHCO₃ followed by acetylchloride (23.4 mL, 329 mmol) stir 1 h. The organic layer was separated,washed with satd NaCl, dried over Na₂SO₄, filtered and solvent removedto yield 8.4 grams of N-(4-fluoro-benzyl)-acetamide.

[0444] N-(4-fluoro-benzyl)-acetamide (697 mg, 4.17 mmol) was suspendedin toluene and treated with 668 mg of 60% NaH (mineral oil) followed by(3-bromopropyl)-benzene (1.27 mL, 8.34 mmol) and the resulting mixturestirred overnight. The mixture was filtered and the solvent removed. Thecrude product was purified by preparative HPLC (C₁₈, MeOH/H₂O-0.1% TFA)to yield 221 mg (19% yield)N-(4-Fluoro-benzyl)-N-(3-phenyl-propyl)-acetamide. HRMS (M+H) calcd forC₁₈H₂₁FNO: 286.1607; found: 286.1603. ¹H NMR and ¹³C NMR show a mixtureof rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.89 (m),2.11 (s), 2.16 (s), 2.60 (t, J=7), 3.19 (dd, J=8, 8), 3.41 (dd, J=8, 8),4.46 (s), 4.54 (s), 6.96-7.32 (overlapping m). ¹³C NMR (125 MHz, CDCl₃)δ: 20.67, 21.21, 28.71, 29.53, 32.77, 33.14, 46.21, 47.25, 48.04, 51.60,115.48, 115.65, 115.95, 116.12, 116.22, 126.04, 126.44, 128.01, 128.07,128.28, 128.46, 128.68, 129.94, 130.01, 131.57, 131.59, 132.61, 132.64,140.32, 141.19, 158.96, 159.28, 161.32, 161.37, 163.28, 163.34, 172.14,172.46.

[0445] Intermediate 43B:3-[(4-Fluoro-benzyl)-(3-phenyl-propyl)-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0446] Intermediate 43B was prepared from Intermediate 43A using MethodIX. HRMS (M+H) calcd for C₂₁H₂₃NO₄F: 372.1611; found: 372.1618. ¹H NMRand ¹³ C NMR show a mixture of rotamers at room temperature. 1H NMR (500MHz, CDCl₃) δ: 1.92 (m), 2. 62 (t, J=7), 3.26 (dd, J=8, 8), 3.44 (dd,J=8, 8), 3.86 (s), 3.89 (s), 4.50 (s), 4.57 (s), 6.17 (s), 6.24 (s),6.97-7.33 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 28.91, 29.89,32.75, 33.18, 45.90, 46.63, 48.08, 50.58, 52.99, 93.57, 115.56, 115.73,115.90, 116.08, 126.11, 126.37, 128.27, 128.32, 128.39, 128.50, 128.68,129.80, 129.87, 131.59, 131.62, 132.43, 132.46, 140.30, 141.07, 159.78,159.86, 161.35, 161.44, 163.27, 163.31, 163.40, 170.78, 171.20.

[0447] Compound 43:3-[(4-Fluoro-benzyl)-(3-phenyl-propyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0448] Compound 43 was prepared from Intermediate 43B using Method XI.HRMS (M−H) calcd for C₂₀H₁₉NO₄F. 356.1298; found: 356.1305. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 1.91 (m), 2.64 (m), 3.26 (dd, J=8, 8), 3.45 (dd, J=7, 7). 4.53(s), 4.57 (s), 6.24 (s), 6.31 (s), 6.97-7.32 (overlapping m). ¹³C NMR(125 MHz, CDCl₃) δ 28.84, 29.88, 32.71, 33.14, 46.08, 46.70, 48.26,50.68, 93.54, 93.66, 115.62, 115.79, 115.98, 116.15, 126.16, 126.46,128.24, 128.27, 128.36, 128.42, 128.52, 128.74, 128.83, 129.85, 129.92,131.29, 132.15, 132.17, 140.15, 140.96, 159.14, 159.31, 161.41, 163.37,165.03, 170.70, 171.16.

EXAMPLE 44

[0449] Intermediate 44A: N-Isopropyl-N-(3-phenyl)-acetamide

[0450] Intermediate 44A was prepared from (3-bromo-propyl)-benzene andisopropyl amine using Method VI. ¹H NMR shows a mixture of rotamers atroom temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.09 (d, J=7), 1.13 (d,J=7), 1.90 (m), 1.98 (s), 2.10 (s), 2.64 (t, J=7), 3.12 (m), 3.19 (m),3.96 (heptet, J=7), 4.65 (heptet, J=7), 7.16-7.32 (overlapping m).

[0451] Intermediate 44B:2-Hydroxy-3-[isopropyl-(3-phenyl-propyl)-carbamoyl]-acrylic Acid MethylEster

[0452] Intermediate 44A was prepared from Intermediate 44B using MethodIX. HRMS (M+H) calcd for C₁₇H₂₄NO₄: 306.1705; found: 306.1699. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.13 (d, J=7), 1.18 (d, J=7), 1.94 (m), 2.67 (m), 3.18(m), 3.29 (m), 3.88 (s), 4.14 (septet, J=7), 4.70 (septet, J=7), 6.06(s), 6.29 (s), 7.14-7.33 overlapping m). ¹³CNMR (125 MHz, CDCl₃) 20.30,21.27, 30.84, 32.34, 33.21, 33.61, 40.96, 42.39, 45.50, 48.58, 52.89,93.60, 94.52, 126.02, 126.34, 126.61, 128.28, 128.34, 128.44, 128.52,128.67, 128.74, 139.47, 140.40, 141.30, 142.04, 159.39, 159.58, 163.50,163.65, 170.38, 170.46.

[0453] Compound 44:2-Hydroxy-3-[isopropyl-(3-phenyl-propyl)-carbamoyl]-acrylic Acid

[0454] Compound 44 was prepared from Intermediate 44B using Method XI.HRMS (M+H) calcd for C₁₆H₂₂NO₄: 292.1549; found: 292.1550. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 1.14 (d, J=7), 1.19 (d, J=7), 1.96 (m), 2.67 (m), 3.18 (m),3.30 (m), 4.14 (heptet, J=7), 4.70 (heptet, J=7), 6.11 (s), 6.35 (s),7.16-7.34 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 20.28, 20.80,21.20, 30.75, 32.28, 33.16, 33.57, 41.14, 42.47, 45.83, 48.79, 93.15,94.40, 117.13, 126.08, 126.42, 128.27, 128.33, 128.47, 128.74, 140.24,141.84, 159.15, 159.57, 165.66, 165.77, 170.41, 177.45.

EXAMPLE 45

[0455] Intermediate 45A: N-(4-Chloro-benzyl)-N-methyl-acetamide

[0456] Intermediate 45A was synthesized from 4-chlorobenzylamine usingthe same procedure as

[0457] Intermediate 34A. HRMS (M+H) calcd for C₁₀H₁₃ClNO: 198.0686;found: 198.0686. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.14 (s), 2.90 (s),2.91 (s), 4.84 (s), 4.53 (s), 7.09-7.34 (overlapping m). ¹³C NMR (125MHz, CDCl₃) δ: 21.46, 21.84, 33.70, 35.58, 50.04, 53.67, 127.69, 128.75,129.16, 129.43, 133.18, 133.51, 135.09, 135.94, 170.78, 170.93.

[0458] Intermediate 45B:3-[(4-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid MethylEster

[0459] Intermediate 45A was prepared from Intermediate 45A using MethodIX. HRMS (M+H) calcd for C₁₃H₁₅NO₄Cl: 284.0690; found: 284.0696. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.01 (s) 3.87 (s), 3.90 (s), 4.56 (s), 4,62 (s), 6.29(s), 7.12-7.31 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.57,34.90, 50.08, 52.70, 53.00, 93.21, 93.49, 117.03, 117.12, 128.01,129.00, 129.29, 129.37, 133.70, 134.08, 134.78, 159.75, 163.24, 170.99.

[0460] Compound 45:3-[(4-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0461] Compound 45 was prepared from Intermediate 45B using Method XI.HRMS (M+H) calcd for C₁₂H₁₃NO₄Cl: 270.0533; found: 270.0536. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 3.02 (s), 4.56 (s), 4.63 (s), 6.36 (s), 7.11-7.36 (overlapping m).

EXAMPLE 46

[0462] Intermediate 46A:N-[3-(4-Fluoro-phenyl)-propyl]-N-methyl-acetamide

[0463] Intermediate 46A was prepared from 3-(4-fluoro-phenyl)-propionicacid using Method II and IV. HRMS (M+H) calcd for C₁₂H₁₆FNO: 210.1294;found: 210.1292. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.83 (m), 2.00 (s), 2.05 (s),2.58 (m), 2.90 (s), 2.94 (s), 3.26 (dd, J=7, 7), 3.39 (dd, J=7, 7), 6.96(m), 7.12 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.19, 21.96, 28.96, 29.87,32.02, 32.36, 33.17, 36.09, 47.15, 50.08, 115.00, 115.17, 115.28,115.45, 129.55, 129.59, 129.61, 129.65, 136.40, 137.28, 160.30, 160.46,162.24, 162.40, 170.37, 170.54.

[0464] Intermediate 46B:3-{[3-(4-Fluoro-phenyl)-propyl]-methyl-carbamoyl}-2-hydroxy-acrylic AcidMethyl Ester

[0465] Intermediate 46B was prepared from Intermediate 45A using MethodIX. HRMS (M+H) calcd for C₁₅H₁₉NO₄F: 296.1298; found: 296.1302. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.89 (m), 2.60 (m), 2.98 (s), 3.02 (s), 3.33 (m), 3.45(m), 3.86 (s), 6.09 (s), 6.20 (s), 6.96 (m), 7.12 (m). ¹³C NMR (125 MHz,CDCl₃) δ: 28.85, 29.88, 31.83, 32.28, 33.54, 35.35, 47.30, 49.25, 52.88,93.36, 93.64, 115.11, 115.27, 115.32, 115.49, 129.59, 129.65, 136.03,136.05, 136.80, 136.82, 159.29, 159.39, 160.38, 160.50, 162.32, 162.44,163.33, 163.36, 170.62, 170.74.

[0466] Compound 46:3-{[3-(4-Fluoro-phenyl)-propyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0467] Compound 46 was prepared from Intermediate 46B using Method XI.HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found: 282.1148. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 1.85-1.96 (overlapping m), 2.61 (m), 3.01 (s), 3.04 (s), 3.36(dd, J=7, 7), 3.47 (dd, J=7, 7), 6.20 (s), 6.28 (s), 6.96 (m), 7.13 (m).¹³C NMR (125 MHz, CDCl₃) δ: 28.80, 29.89, 31.84, 32.26, 33.81, 35.49,44.81, 47.55, 49.49, 93.54, 93.64, 115.15, 115.32, 115.38, 115.55,129.58, 129.64, 135.95, 136.70, 142.04, 158.81, 159.02, 160.41, 160.54,162.35, 162.48, 165.43, 170.54, 171.68.

EXAMPLE 47

[0468] Intermediate 47A:N-(4-Fluoro-benzyl)-N-(2-phenoxy-ethyl)-acetamide

[0469] Intermediate 47A was prepared from (2-chloro-ethoxy)-benzene and4-fluorobenzyl amine using Method VI. ¹H NMR and ¹³C NMR show a mixtureof rotamers at room temperature. 1H NMR (500 MHz, CDCl₃) δ: 2.13 (s),2.29 (s), 3.64 (t, J=5), 3.73 (t, J=5), 4.02 (t, J=5), 4.17 (t, J=5),4.67 (s), 4.69 (s), 6.82-7.30 (overlapping m). ¹³C NMR (125 MHz, CDCl₃)δ: 21.77, 21.81, 45.73, 47.12, 48.00, 53.17, 65.35, 66.50, 114.34,115.38, 115.56, 115.79, 115.96, 120.99, 121.42, 128.03, 128.09, 129.55,129.63, 129.67, 129.74, 132.60, 132.62, 133.38, 133.41, 158.14, 158.46,161.20, 161.26, 163.15, 163.21, 171.26, 171.32.

[0470] Intermediate 47B:3-[(4-Fluoro-benzyl)-(2-phenoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0471] Intermediate 47B was prepared from Intermediate 47A using MethodIX. HRMS (M+H) calcd for C₂₀H₂₁NO₅F: 374.1404; found: 374.1412. ¹H NMR(500 MHz, CDCl₃) δ: 3.71 (t, J=5), 3.80 (t, J=5), 3.85 (s), 3,90 (s),4.12 (t, J=5), 4.20 (t, J=50, 4.76 (s), 6.27 (s), 6.44 (s), 6.86 (m),6.99 (m), 7.17 (m), 7.29 (m). 0 NMR (125 MHz, CDCl₃) δ: 45.82, 46.37,48.85, 52.23, 53.00, 53.01, 65.74, 66.14, 93.55, 93.94, 114.33, 115.65,115.82, 115.91, 116.08, 117.05, 117.11, 121.24, 121.53, 128.41, 128.47,129.61, 129.66, 129.79, 129.85, 131.70, 131.72, 132.35, 132.37, 157.95,158.23, 159.68, 159.99, 161.41, 161.45, 163.11, 163.25, 163.36, 163.41,171.37, 171.60.

[0472] Compound 47:3-{(4-Fluoro-benzyl)-[2-(4-fluoro-phenoxy)-ethyl]-carbamoyl}-2-hydroxy-acrylicAcid

[0473] Compound 47 was prepared from Intermediate 47B using Method XI.HRMS (M+H) calcd for C₁₉H₁₈NO₅F₂: 378.1153; found: 378.1151. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 3.71 (m), 3.83 (m), 4.04 (m), 4.12 (m), 4.75 (s), 4.76 (s), 6.34 (s),6.51 (s), 6.75-7.27 (overlapping m).

EXAMPLE 48

[0474] Intermediate 48A: N-(3-Bromo-4-fluoro-benzyl)-N-methyl-acetamide

[0475] Intermediate 48A was prepared from 3-bromo-4-fluoro-benzoic acidusing Methods II and IV. HRMS (M+H) calcd for C₁₀H₁₂BrFNO: 260.0086;found: 260.0085. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 2. 13 (s), 2.14 (s), 2.91 (s),2.92 (s), 4.47 (s), 4.50 (s), 7.03-7.43 (overlapping m). ¹³C NMR (125MHz, CDCl₃) δ: 21.44, 21.80, 33.68, 35.65, 49.61, 53.13, 99.71, 109.05,109.21, 109.84, 116.45, 116.63, 116.90, 117.07, 126.81, 126.87, 128.64,128.70, 131.38, 132.96, 134.03, 134.91, 134.94, 157.43, 157.55, 159.39,159.52, 170.86.

[0476] Intermediate 48B:3-[(3-Bromo-4-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic AcidMethyl Ester

[0477] Intermediate 48B was prepared from Intermediate 48A using MethodIX. HRMS (M+H) calcd for C₁₃H₁₄NO₄FBr: 346.0090; found: 346.0092. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 3.01 (s), 3.02 (s), 3.70 (s), 3.89 (s), 4.54 (s), 4.59(s), 6.26 (s), 6.29 (s), 7.10 (m), 7.19 (m), 7.36 (m), 7.44 (m). ¹³C NMR(125 MHz, CDCl₃) δ: 33.55, 34.95, 49.60, 52.13, 53.01, 92.98, 93.43,109.32, 109.48, 109.78, 109.95, 116.72, 116.89, 117.04, 117.08, 117.72,117.21, 127.14, 127.20, 128.62, 128.68, 131.74, 133.02, 133.80, 133.84,157.68, 159.65, 159.82, 159.97, 163.17, 171.02, 171.21.

[0478] Compound 48:3-[(3-Bromo-4-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0479] Compound 48 was prepared from Intermediate 48B using Method XI.HRMS (M−H) calcd for C₁₂H₁₀NO₄BrF: 329.9777; found: 329.9784. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.03 (s), 3.04 (s), 4.55 (s), 4.60 (s), 6.34 (s), 6.36 (s),7.10 (m), 7.18 (m), 7.37 (m), 7.45 (m). ¹³C NMR (125 MHz, CDCl₃) δ:33.75, 35.04, 49.78, 52.23, 93.29, 93.75, 109.38, 109.55, 116.77,116.95, 117.28, 127.26, 128.66, 128.72, 131.78, 132.76, 133.07, 133.51,133.54, 157.75, 159.05, 159.72, 165.10, 170.92, 171.12.

EXAMPLE 49

[0480] Intermediate 49A:N-(4-Fluoro-benzyl)-N-[2-(4-fluoro-phenoxy)-ethyl]-acetamide

[0481] Intermediate 49A was prepared from1-(2-Bromo-ethoxy)-4-fluoro-benzene and 4-fluorobenzylamine using MethodVI. HRMS (M+H) calcd for C₁₇H₁₈F₂NO: 306.1351; found: 306.1298. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 2.13 (s), 2.28 (s), 3.63 (t, J=5), 3.71 (t, J=5), 3.96(t, J=5), 4.11 (t, J=5), 6.74-7.24 (overlapping m). ¹³C NMR (125 MHz,CDCl₃) δ: 21.75, 21.80, 45.78, 47.15, 48.04, 53.18, 66.11, 67.07,115.24, 115.31, 115.35, 115.41, 115.56, 115.79, 115.81, 115.92, 115.98,116.10, 127.98, 128.05, 129.64, 129.70, 132.52, 132.54, 133.35, 133.37,154.28, 154.59, 154.60, 156.39, 156.61, 158.28, 158.52, 161.20, 161.27,163.16, 163.23, 171.24, 171.35.

[0482] Intermediate 49B:3-{(4-Fluoro-benzyl)-[2-(4-fluoro-phenoxy)-ethyl]-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0483] Intermediate 49B was prepared from Intermediate 49A sing MethodIX. HRMS (M+H) calcd for C₂₀H₂₀NO₅F: 392.1310; found: 392.1319. Analcalcd for C₂₀H₁₉NO₅F: C, 61.38; H, 4.89; N, 3.57; found: C, 61.28; H,4.82; N, 3.50. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.70 (t, J=5), 3.80 (t, J=5),3.85 (s), 3.90 (s), 4.03 (t, J=5), 4.15 (t J=5), 4.74 (s), 4.75 (s),6.28 (s), 6.42 (s), 6.78 (m), 6.95-7.07 (overlapping m), 7.24 (m), 7.26(m). ¹³C NMR (125 MHz, CDCl₃) δ: 45.88, 46.39, 48.87, 52.25, 53.01,53.03, 66.43, 66.77, 93.50, 93.88, 115.292, 115.36, 115.43, 115.66,115.83, 115.87, 115.93, 115.95, 116.06, 116.11, 116.14, 128.36, 128.43,129.75, 129.82, 131.63, 132.32, 154.08, 154.36, 156.52, 158.42, 158.58,159.71, 160.04, 161.47, 163.08, 163.24, 163.38, 163.43, 171.37, 171.63.

[0484] Compound 49:3-[(4-Fluoro-benzyl)-(2-phenoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0485] Compound 49 was prepared from Intermediate 49B using Method XI.HRMS (M−H) calcd for C₁₉H₁₇NO₅F: 358.1091; found: 358.1098. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.72 (m), 3.82 (m), 4.09 (m), 4.21 (m), 6.35 (s), 6.53 (s),6.86 (m), 7.04 (overlapping m), 7.17 (m), 7.27 (m). ¹³C NMR (125 MHz,CDCl₃) δ: 45.97, 46.48, 49.05, 52.33, 65.72, 66.04, 93.74, 94.14,114.33, 115.71, 115.89, 115.99, 116.16, 121.31, 121.60, 128.43, 128.50,129.63, 129.68, 129.76, 129.83, 129.89, 131.40, 132.05, 157.88, 158.17,158.81, 159.15, 161.46, 161.50, 163.42, 163.47, 164.65, 164.77, 171.32,171.52.

EXAMPLE 50

[0486] Intermediate 50A:N-[1-(4-Fluoro-phenyl)-ethyl]-N-methyl-acetamide

[0487] Intermediate 50A was prepared 1-(4-fluoro-phenyl)-ethyl amineusing the same method as Intermediate 34A. HRMS (M+H) calcd forC₁₁H₁₅FNO: 196.1138; found: 196.1139. ¹H NMR and ¹³C NMR show a mixtureof rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.44 (d,J=7), 1.57 (d, J=7), 2.11 (s), 2.22 (s), 2.63 (s), 5.05 (q, J=7), 6.02(q, J=7), 7.00 (overlapping m), 7.23 (overlapping m). ¹³C NMR (125 MHz,CDCl₃) δ: 15.76, 17.72, 21.75, 22.31, 27.57, 30.05, 49.40, 55.15,115.14, 115.31, 115.51, 115.69, 128.11, 128.86, 135.96, 136.46, 160.98,161.09, 162.933, 163.06, 170.42, 170.63.

[0488] Intermediate 50B:3-{[1-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic AcidMethyl Ester

[0489] Intermediate 50B was prepared from Intermediate 50A using MethodIX. HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found: 282.1141. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.52 (d, J=7), 1.63 (d, J=7), 2.71 (s), 2.72 (s), 3.89(s), 5.24 (q, J=7), 6.03 (q, J=7), 6.24 (s), 6.45 (s), 7.04 (m), 7.26(m). ¹³C NMR (125 MHz, CDCl₃) δ: 15.81, 17.56, 27.69, 29.47, 49.73,52.97, 54.19, 93.10, 94.04, 115.45, 115.62, 115.70, 115.87, 128.41,128.47, 128.91, 128.97, 135.34, 135.37, 159.63, 159.96, 161.22, 163.18,163.34, 163.43, 170.75.

[0490] Compound 50:3-{[1-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0491] Compound 50 was prepared from Intermediate 50B using Method XI.HRMS (M−H) calcd for C₁₃H₁₃NO₄F: 266.0829; found: 266.0835. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 1.53 (d, J=7), 1.64 (d, J=7), 2.74 (s), 5.25 (q, J=7), 6.02(q, J=7), 6.31 (s), 6.52 (s), 7.05 (m), 7.21-7.27 (overlapping m), ¹³CNMR (125 MHz, CDCl₃) δ: 15.81, 17.54, 27.94, 29.56, 50.09, 54.42, 93.04,94.09, 115.52, 115.69, 115.77, 115.90, 115.94, 128.43, 128.50, 128.93,128.99, 134.59, 135.04, 135.07, 159.08, 159.49, 161.28, 163.24, 165.22,170.66, 170.71.

EXAMPLE 51

[0492] Intermediate 51A:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-[3-(2-fluoro-phenyl)-propyl]-acetamide

[0493] Intermediate 51A was prepared from4-(Fluoro-benzyl)-[3-(2-fluoro-phenyl)-propyl]-amine hydrochloride usingMethod XIV. MS (M+H) calcd for C₂₃H₂₄F₂NO₄: 416.2; found: 416.0. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (300 MHz, CDCl₃)δ: 1.71 (s), 1.73 (s), 1.87 (m), 2.62 (m), 3.28 (m), 3.44 (m), 4.53 (s),4.58 (s), 6.08 (s), 6.93-7.21 (overlapping m).

[0494] Compound 51:3-{(4-Fluoro-benzyl)-[3-(2-fluoro-phenyl)-propyl]-carbamoyl}-2-hydroxy-acrylicAcid

[0495] Compound 51 was prepared from Intermediate 51A using MethodXVIII. MS (M−H) calcd for C₂₀H₁₈NO₄F₂: 372.12; found: 374.01. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz,d₆-MeOD) δ: 1.86 (m), 2.65 (m), 3.34 (m), 3.47 (m), 3.72 (m), 4.61 (s),4.63 (s), 6.21 (s), 6.29 (s), 6.98-7.26 (overlapping m).

EXAMPLE 52

[0496] Intermediate 52A:2-(2,2-Dimethyl-5-oxo[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(2-phenyl-cyclopropylmethyl)-acetamide

[0497] Intermediate 52A was prepared from(4-fluoro-benzyl)-(2-phenyl-cyclopropylmethyl)-amine hydrochloride usingMethod XIV. MS (M+H) calcd for C₂₄H₂₅FNO₄: 410.2; found: 410.1.

[0498] Compound 52:3-[(4-Fluoro-benzyl)-(2-phenyl-cyclopropylmethyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0499] Compound 52 was prepared from Intermediate 52A using MethodXVIII. MS (M−H) calcd for C₂₁H₁₉NO₄F: 368.13; found: 368.06. ¹H NMR and¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,d₆-MeOD) δ: 0.92 (m), 1.28 (m), 1.85 (m), 3.39-3.65 (overlapping m),4.73 (s), 6.25 (s), 6.46 (s), 6.92-7.29 (overlapping m). ¹³C NMR (125MHz, d₆-MeOD) δ: 14.96, 15.19, 22.98, 23.11, 23.41, 23.53, 23.73, 49.73,49.92, 51.29, 51.99, 52.35, 95.20, 95.24, 116.27, 116.45, 116.51,116.63, 116.69, 126.64, 126.72, 126.81, 129.35, 129.39, 129.52, 129.58,130.45, 130.52, 130.84, 130.91, 134.61, 143.28, 143.78, 160.78, 160.82,162.89, 164.63, 165.51, 165.63, 172.42, 172.95.

EXAMPLE 53

[0500] Intermediate 53A: 2-(2,2-Dimethyl-5-oxo[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-naphthalen-2-ylmethyl-acetamide

[0501] Intermediate 53A was prepared from (4-fluoro-benzyl)-naphthalen-2-ylmethyl-amine hydrochloride using Method XIV. ¹H NMR shows a mixtureof rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.73 (s),1.76 (s), 4.50 (s), 4.66 (s), 4.67 (s), 4.79 (s), 6.21 (s), 6.24 (s),7.00-7.86 (overlapping m).

[0502] Compound 53:3-[(4-Fluoro-benzyl)-naphthalen-2-ylmethyl-carbamoyl]-2-hydroxy-acrylicAcid

[0503] Compound 53 was prepared from Intermediate 53A using MethodXVIII. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR(500 MHz, d₆-MeOD) δ: 4.57 (s), 4.70 (s), 4.77 (s), 4.82 (s), 6.39 (s),6.42 (s), 7.01-7.85 (overlapping m).

EXAMPLE 54

[0504] Intermediate 54A: 2-(2,2-Dimethl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-N-naphthalen-2-ylmethyl-acetamide

[0505] Intermediate 54A was prepared from methyl-naphthalen-2-ylmethyl-amine hydrochloride using Method XVII. ¹H NMR shows mixtureof rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.69 (s),1.76 (s), 3.03 (s), 3.05 (s), 4.75 (s) 4.82 (s) 6.21 (s) 6.22 (s),7.28-7.85 (overlapping m).

[0506] Compound 54:2-Hydroxy-3-(methyl-naphthalen-2-ylmethyl-carbamoyl)-acrylic Acid

[0507] Compound 54 was prepared from Intermediate 54A using MethodXVIII. MS (M−H) calcd C₁₆H₁₄NO₅: 284.09; found: 284.07. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ:3.33 (s), 3.34 (s), 4.82 (s), 6.40 (s), 6.44 (s), 7.33-7.88 (overlappingm).

EXAMPLE 55

[0508] Intermediate 55A:N-(4-Chloro-phenyl)-2-(2,2-deimethyl-5-oxo-[1,3]-4-ylidene)-N-naphthalen-2-ylmethyl-acetamide

[0509] Intermediate 55A was prepared from(4-chloro-phenyl)-naphthalen-2-ylmethyl-amine hydrochloride using MethodXVII. MS (M+H) calcd for C₂₄H₂₁ClNO₄: 422.1; found: 422.1. ¹H NMR (500MHz, d₆-MeOD) δ: 1.69 (s, 6), 5.15 (s, 2), 5.62 (s, 1), 7.11-7.82(overlapping m, 11).

[0510] Compound 55:3-[(4-Chloro-phenyl)-naphthalen-2-ylmethyl-carbamoyl]-2-hydroxy-acrylicAcid

[0511] Compound 55 was prepared from Intermediate 55A using MethodXVIII. MS (M−H) calcd for C₂₁H₁₅NO₄Cl: 380.07; found: 380.07. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, DMSO)δ: 5.04 (s), 5.14 (s), 5.59 (br s), 7.23-7.88 (overlapping m).

EXAMPLE 56

[0512] Intermediate 56A:N-(4-Chloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-phenyl-propyl)-acetamide

[0513] Intermediate 56A was prepared from(4-chloro-phenyl)-(3-phenyl-propyl)-amine hydrochloride using MethodXVII. MS (M+H) calcd for C₂₂H₂₃ClNO₄: 400.1; found: 400.1.

[0514] Compound 56:3-[(4-Chloro-phenyl)-(3-phenyl-propyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0515] Compound 56 was prepared from Intermediate 56A using MethodXVIII. MS (M−H) calcd for C₁₉H₁₇NO₄Cl: 358.08; found: 358.02.

EXAMPLE 57

[0516] Intermediate 57A: N,N-Bis(4-chloro-benzyl)-acetamide

[0517] Intermediate 57A was prepared from 4-chlorobenzylamine and4-chlorobenzylbromide using the same method as intermediate 43A. HRMS(M+H) calcd for C₁₆H₁₆Cl₂NO: 308.0609; found: 308.0611. ¹H NMR (500 MHz,CDCl₃) δ: 2.20 (s, 3), 4.39 (s, 2), 4.52 (s, 2), 7.07 (d, 2, J=8), 7.14(d, 2, J=8), 7.27 (d, 2, J 8), 7.34 (d, 2, J=8). ¹³C NMR (125 MHz,CDCl₃) δ: 21.70, 47.41, 50.31, 127.78, 128.83, 129.25, 129.72, 133.41,133.66, 134.67, 135.63, 171.07.

[0518] Intermediate 57B:3-[Bis-(4-chloro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0519] Intermediate 57B was prepared from Intermediate 57A using MethodIX. HRMS (M+H) calcd for C₁₉H₁₈NO₄Cl₂: 394.0613; found: 394.0602. ¹H NMR(500 MHz, CDCl₃) δ: 3.87 (s, 3), 4.46 (s, 2), 4.58 (s, 2), 6.30 (s, 1),7.08 (d, 2, J=8), 7.16 (d, 2, J=8), 7.31 (d, 2, J=8), 7.34 (d, 2, J=8).¹³C NMR (125 MHz, CDCl₃) δ: 47.54, 49.50, 53.05, 93.21, 128.10, 129.04,129.34, 129.65, 133.79, 133.66, 134.09, 134.58, 160.39, 163.04, 171.46.

[0520] Compound 57:3-[Bis-(4-chloro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0521] Compound 57 was prepared from Intermediate 57B using MethodXVIII. HRMS (M−H) calcd for C₁₈H₁₄NO₄Cl₂: 378.0300; found: 378.0297.Anal calcd for C₁₈H₁₅NO₄Cl₂: C, 56.86, H, 3.97; N, 3.68; found: C,57.04; H, 4.02; N, 3.60. ¹H NMR (500 MHz, DMSO) δ: 4.62 (s, 2), 4.69 (s,2), 6.23 (s, 1), 7.21-7.44 (overlapping m, 8). ¹³C NMR (125 MHz, DMSO)δ: 48.14, 49.65, 93.21, 128.31, 128.39, 128.63, 129.64, 131.90, 131.94,135.68, 135.76, 160.39, 163.24, 171.36.

EXAMPLE 58

[0522] Intermediate 58A:(3-Chloro-4-fluoro-benzyl)-methyl-amine

[0523] Intermediate 58A was formed from 4-fluoro-3-chloro-benzaldehydeusing Method III. HRMS (M+H) calcd for C₈H₁₀NClF: 174.0486; found:174.0481. ¹H NMR (500 MHz, CDCl₃) δ: 2.43 (s, 3), 3.69 (s, 2), 7.07 (m,1), 7.17 (m, 1), 7.37 (m, 1). ¹³C NMR (125 MHz, CDCl₃) δ: 35.96, 54.87,116.27, 116.44, 120.68, 120.82, 127.70, 127.75, 130.19, 137.32, 137.35,156.15, 158.11.

[0524] Intermediate 58B:N-(3-Chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0525] Intermediate 58B was prepared from Intermediate 58A using MethodXVII. HRMS (M+H) calcd for C₁₅H₁₆NO₄ClF: 328.0752; found: 328.0755. ¹HNMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR(500 MHz, CDCl₃) δ: 1.72 (s), 1.74 (s), 2.96 (s), 3.01 (s), 4.53 (s),4.58 (s), 6.09 (s), 6.16 (s), 7.06-7.34 (overlapping m). ¹³C NMR (125MHz, CDCl₃) δ: 26.78, 26.85, 33.28, 35.37, 49.71, 52.88, 96.68, 96.87,113.89, 113.96, 116.65, 116.82, 117.03, 117.19, 121.11, 121.26, 121.67,121.81, 126.33, 126.39, 127.95, 128.01, 128.77, 130.20, 133.99, 134.02,144.85, 144.95, 156.55, 158.53, 162.31, 162.42, 164.08, 164.30.

[0526] Compound 58:3-[(3-Chloro-4-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0527] Compound 58 was prepared from Intermediate 58B using MethodXVIII. HRMS (M−H) calcd for C₁₂H₁₀NO₄ClF: 286.0282; found: 286.0281. ¹HNMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR(500 MHz, CDCl₃) δ: 3.03 (s), 3.04 (s), 4.55 (s), 4.60 (s), 6.34 (s),6.37 (s), 7.10-7.32 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.74,35.03, 49.89, 52.32, 93.17, 93.63, 116.92, 117.08, 117.27, 117.44,121.39, 121.53, 126.36, 126.42, 127.81, 127.87, 128.91, 130.22, 133.13,133.16, 156.77, 158.75, 159.09, 159.27, 164.97, 170.95, 171.16.

EXAMPLE 59

[0528] Intermediate 59A: (3, 4-Difluoro-benzyl)-methyl-amine;Hydrochloride

[0529] Intermediate 59A was prepared from 3,4-difluorobenzaldehyde usingMethod III. HRMS (M+H) calcd for C₈H₁₀NF₂ 158.0781; found: 158.0783. ¹HNMR (500 MHz, d₆-MeOD) δ: 1.18 (s, 3), 2.66 (s, 2), 5.82 (m, 2), 5.98(m, 1). ¹³C NMR (125 MHz, d₆-MeOD) δ: 31.74, 50.87, 117.67, 117.69,117.80, 118.82, 118.93, 118.97, 126.71, 126.75, 126.80, 128.49, 128.54,128.58, 149.07, 149.19, 149.80, 149.92, 151.06, 151.18, 151.80, 151.92.

[0530] Intermediate 59B:N-(3,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0531] Intermediate 59B was prepared from Intermediate 59A using MethodXVII. HRMS (M+H) calcd for C₁₅H₁₆NO₄F₂: 312.1048; found: 312.1042. ¹HNMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 1.70 (s), 1.73 (s), 1.74 (s), 2.97 (s), 3.02 (s), 4.53 (s),4.58 (s), 6.09 (s), 6.16 (s), 7.00-7.13 (overlapping m).

[0532] Compound 59:3-[(3,4-Difluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0533] Compound 59 was prepared from Intermediate 59B using MethodXVIII. HRMS (M−H) calcd for C₁₂H₁₀NO₄F₂: 270.0578; found: 270.0581. ¹HNMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.04 (s), 4.55 (s), 4.61 (s), 6.34 (s), 6.37 (s), 6.90-7.19(overlapping m).

EXAMPLE 60

[0534] Intermediate 60A: (4-Fluoro-3-methoxy-benzyl)-methyl-amine

[0535] Intermediate 60A was prepared from 4-fluoro-3-methoxybenzaldehydeusing Method III. HRMS (M+H) calcd for C₉H₁₃NOF: 170.0981; found:170.0984. ¹H NMR (500 MHz, CDCl₃) δ: 2.44 (s, 33.69 (s, 2), 3.88 (s, 3),6.80 (m, 1), 6.95-7.01 (overlapping m, 2). ¹³C NMR (125 MHz, CDCl₃) δ:36.06, 55.76, 56.17, 113.17, 115.54, 115.69, 120.25, 120.30, 136.52,136.55, 147.49, 147.57, 150.53, 152.47.

[0536] Intermediate 60B:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-3-methoxy-benzyl)-N-methyl-acetamide

[0537] Intermediate 60B was prepared from Intermediate 60A using MethodXVII. HRMS (M+H) calcd for C₁₆H₁₉NO₅F: 324.1247; found: 324.1239. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.69 (s), 1.72 (s), 2.97 (s), 2.99 (s), 3.85 (s), 3.86(s), 4.52 (s), 4.58 (s), 6.13 (s), 6.16 (s), 6.79-7.04 (overlapping m).¹³C NMR (125 MHz, CDCl₃) δ: 26.77, 26.84, 33.36, 35.12, 50.25, 53.50,56.34, 96.99, 97.06, 111.69, 113.45, 113.79, 113.83, 115.82, 115.96,116.33, 116.48, 118.78, 118.83, 120.61, 120.67, 132.43, 132.46, 133.22,133.25, 144.74, 144.80, 147.81, 147.89, 148.14, 150.96, 152.92, 162.42,162.51, 163.94, 164.31.

[0538] Compound 60:3-[(4-Fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0539] Compound 60 was prepared from Intermediate 60B using MethodXVIII. HRMS (M−H) calcd for C₁₃H₁₃NO₅F: 282.0778; found: 282.0774. Analcalcd for C₁₃H₁₄NO₅F: C, 55.12; H, 4.98; N, 4.94; found: C, 55.15; H,5.05; N, 4.81. ¹H NMR and ¹³C NMR show a mixture of rotamers at roomtemperature. ¹H NMR (500 MHz, DMSO) δ: 2.97 (s), 3.02 (s), 3.83 (s),4.58 (s), 4.65 (s), 6.26 (s), 6.28 (s), 6.72-7.20 (overlapping m). ¹³CNMR (125 MHz, DMSO) δ: 33.48, 34.70, 49.36, 51.85, 55.77, 93.00, 93.10,112.34, 113.26, 115.61, 115.75, 115.85, 115.99, 118.26, 118.31, 119.67,119.73, 133.34, 146.94, 147.03, 147.09, 147.18, 149.78, 151.72, 160.00,163.42, 170.61, 170.93.

EXAMPLE 61

[0540] Intermediate 61A: (4-Fluoro-3-methyl-benzyl)-methyl-amine

[0541] Intermediate 61A was prepared from4-fluoro-3-methyl-benzylbromide using Method I. LC/MS (M+H) calcd forC₉H₁₃NF: 154.1; found: 154.1. ¹H NMR (500 MHz, CDCl₃) δ: 2.25 (s, 3),2.44 (s, 3), 3.67 (s, 2), 6.94 (m, 1), 7.08 (m, 1), 7.14 (m).

[0542] Intermediate 61B:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-3-methyl-benzyl)-N-methyl-acetamide

[0543] Intermediate 61B was prepared from Intermediate 61A using MethodXVII. HRMS (M+H) calcd for C₁₆H₁₉NO₄F: 308.1298; found: 308.1302. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.70 (s), 1.73 (s), 2.24 (s), 2.25 (s), 2.95 (s), 2.98(s), 4.50 (s), 4.57 (s), 6.14 (s), 6.16 (s), 6.91-7.11 (overlapping m).¹³ C NMR (125 MHz, CDCl₃) δ: 14.52, 14.55, 14.60, 26.79, 26.86, 33.22,35.12, 49.92, 53.26, 97.03, 97.28, 113.74, 113.84, 114.95, 115.13,115.34, 115.52, 125.05, 125.18, 125.48, 125.55, 125.60, 127.16, 127.22,129.59, 129.63, 131.32, 131.36, 131.45, 132.29, 144.68, 144.76, 159.83,161.77, 162.47, 162.58, 163.88, 164.25.

[0544] Compound 61:3-[(4-Fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0545] Compound 61 was prepared from Intermediate 61B using MethodXVIII. HRMS (M−H) calcd for C₁₃H₁₃NO₄F: 266.0828; found: 266.0826. ¹HNMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR(500 MHz, CDCl₃) δ: 2.26 (s), 3.01 (s), 4.52 (s), 4.59 (s), 6.36 (s),6.39 (s), 6.98-7.29 (overlapping m). ¹³C NMR (125 Hz, CDCl₃) δ: 14.60,33.64, 34.84, 50.17, 52.78, 93.47, 93.64, 115.23, 115.41, 115.55,115.73, 125.37, 125.51, 125.69, 125.88, 127.05, 129.79, 130.64, 131.19,131.37, 159.10, 160.03, 160.01, 165.16, 170.81, 171.06.

EXAMPLE 62

[0546] Intermediate 62A: (3-Chlorobenzyl)-methylamine

[0547] Intermediate 62A was prepared from 3-chloro-benzylbromide usingMethod I. LC/MS (M+H) calcd for C₈H₁₁NCl; 156.1; found: 156.1. ¹H NMR(500 MHz, CDCl₃) δ: 2.44 (s, 3), 3.72 (s, 2), 7.23 (m, 3), 7.32 (s, 1)

[0548] Intermediate 62B: N-(3-Chloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0549] Intermediate 62B was prepared from Intermediate 62A using MethodXVII. HRMS (M+H) calcd for C₁₅H₁₇NO₄Cl; 310.0846; found: 310.0845. ¹HNMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR(500 MHz, CDCl₃) δ: 1.63 (s), 1.68 (s), 2.92 (s) 2.96 (s), 4.50 (s),4.56 (s), 6.05 (s), 6.11 (s), 7.09-7.23 (overlapping m). ¹³C NMR (125MHz, CDCl₃) δ: 27.03, 27.12, 33.63, 35.65, 50.42, 53.68, 97.15, 97.41,114.07, 114.16, 125.04, 126.56, 126.94, 128.02, 128.30, 128.37, 130.23,130.52, 134.84, 135.27, 138.56, 139.19, 144.94, 145.06, 162.61, 162.73,164.35, 164.65.

[0550] Compound 62:3-[(3-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0551] Compound 62 was prepared from Intermediate 62B using MethodXVIII. HRMS (M−H) calcd for C₁₂H₁₁NO₄Cl; 268.0377; found: 268.0384. ¹HNMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR(500 MHz, CDCl₃) δ: 3.04 (s), 4.57 (s), 4.63 (s), 6.35 (s), 6.37 (s),7.14-7.32 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) 33.83, 35.09, 50.37,52.85, 93.26, 93.55, 124.75, 129.09, 126.77, 128.00, 128.13, 128.22,128.39, 128.44, 130.19, 130.29, 130.47, 134.77, 135.13, 137.42, 138.06,159.22, 164.93, 171.01, 171.24.

EXAMPLE 63

[0552] Intermediate 63A: (4′-Fluoro-biphenyl-3-ylmethyl)-methyl-amine

[0553] Intermediate 63A was prepared from4′-fluoro-biphenyl-3-carbaldehyde using Method III. LC/MS (M+H) calcdC₁₄H₁₅NF; 216.1; found: 216.2. ¹H NMR (500 MHz, CDCl₃) δ: 2.50 (s, 3),3.82 (s, 2), 7.11 (m, 2), 7.30 (m, 1), 7.38-7.57 (overlapping m, 5). ¹³CNMR (125 MHz, CDCl₃) δ: 36.17, 56.13, 115.51, 115.68, 125.71, 126.88,127.14, 128.71, 128.78, 128.91, 137.29, 140.41, 140.81.

[0554] Intermediate 63B:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4′-fluoro-biphenyl-3-ylmethyl)-N-methyl-acetamide

[0555] Intermediate 63B was prepared from Intermediate 63A using MethodXVII. HRMS (M+H) calcd for C₂₁H₂₁NO₄F: 370.1455; found: 370.1450. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.67 (s), 1.73 (s), 3.03 (s), 4.65 (s), 4.72 (s), 6.18(s), 6.19 (s), 7.10-7.54 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ:26.75, 26.85, 33.49, 35.30, 50.60, 65.91, 97.11, 97.35, 113.75, 113.83,115.56, 115.67, 115.73, 115.84, 125.10, 125.43, 126.29, 126.59, 126.79,127.15, 128.77, 128.83, 129.18, 129.49, 136.83, 136.99, 137.51, 140.76,141.11, 144.70, 162.56, 164.03, 164.45.

[0556] Compound 63:3-[(4′-Fluoro-biphenyl-3-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylicAcid

[0557] Compound 63 was prepared from Intermediate 63B using MethodXVIII. HRMS (M−H) calcd for C₁₈H₁₅NO₄F; 328.0985; found: 328.0989. Anal.Calcd for C₁₈H₁₆NO₄F: C, 65.64; H, 4.89; N, 4.25; found: C, 65.39; H,5.27; N, 4.00.

EXAMPLE 64

[0558] Intermediate 64A: Methyl-(3-phenoxy-benzyl)-amine

[0559] Intermediate 64A was prepared from 3-phenoxy-benzylbromide usingMethod I. LC/MS (M+H) calcd for C₁₄H₁₆NO: 214.1; found: 214.2. ¹H NMR(500 MHz, CDCl₃) δ: 2.45 (s, 3), 3.74 (s, 2), 6.90 (m, 1), 7.00-7.35(overlapping m, 8).

[0560] Intermediate 64B:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-N-(3-phenoxy-benzyl)-acetamide

[0561] Intermediate 64B was prepared from Intermediate 64A using MethodXVII. LC/MS (M+H) calcd C₂₁H₂₂NO₅: 368.1; found: 368.2. HRMS calcd forC₂₁H₂₂NO₅: 368.1498; found: 368.1498. ¹H NMR and ¹³C NMR show a mixtureof rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.69 (s),1.72 (s), 2.99 (s), 3.01 (s), 4.55 (s), 4.64 (s), 6.13 (s), 6.17 (s),6.85-7.36 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 26.78, 26.84,33.42, 39.32, 50.31, 53.66, 97.04, 97.28, 113.76, 113.83, 116.98,117.80, 117.94, 118.59, 118.78, 119.03, 121.12, 122.92, 123.33, 123.61,129.80, 129.88, 130.02, 130.31, 138.28, 138.91, 144.70, 156.78, 157.11,157.48, 157.99, 162.55, 164.01, 164.35.

[0562] Compound 64:2-Hydroxy-3-[methyl-(3-phenoxy-benzyl)-carbamoyl]-acrylic Acid

[0563] Compound 64 was prepared from Intermediate 64B using MethodXVIII. LC/MS (M+H) calcd for C₁₈H₁₈NO₅: 328.1; found: 328.1. HRMS (M−H)calcd for C₁₈H₁₆NO₅: 326.1029; found: 326.1034 ¹H NMR shows a mixture ofrotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 3.03(s), 4.55 (s), 4.63 (s), 6.35 (s), 6.80-7.37 (overlapping m)

EXAMPLE 65

[0564] Intermediate 65A: (3,4-Dimethylbenzyl)-methylamine

[0565] Intermediate 65A was prepared from 3,4-dimethylbenzaldehyde usingMethod III. HRMS (M+H) calcd for C₁₀H₁₆N; 150.1282; found: 150.1287. ¹HNMR (500 MHz, CDCl₃) δ: 2.25 (s, 3), 2.27 (s, 3), 2.45 (s, 3), 3.69 (s,2), 7.04-7.11 (m, 3). ¹³C NMR (125 MHz, CDCl₃) δ: 19.43, 19.74, 36.08,55.88, 125.62, 129.59, 129.61, 135.18, 136.57, 137.63.

[0566] Intermediate 65B:N-(3,4-Dimethyl-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0567] Intermediate 65B was prepared from Intermediate 65A using MethodXVII. LC/MS (M+H) calcd for C₁₇H₂₂NO₄: 304.2; found: 304.3. HRMS (M+H)calcd for C₁₇H₂₂NO₄; 304.1549; found: 304.1552.

[0568] Compound 65:3-[(3,4-Dimethyl-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0569] Compound 65 was prepared from Intermediate 65B using MethodXVIII. LC/MS (M+H) calcd for C₁₄H₁₈NO₄; 264.1; found: 264.3.

EXAMPLE 66

[0570] Intermediate 66A: (4-Methoxy-3-methylbenzyl)-methylamine

[0571] Intermediate 66A was prepared from4-methoxy-3-methyl-benzaldehyde using Method III. HRMS (M+H) calcd forC₁₀H₁₆NO; 166.1232; found: 166.1235. ¹H NMR (500 MHz, CDCl₃) δ: 2.23 (s,3), 2.46 (s, 3), 3.67 (s, 2), 3.82 (s, 3), 6.77 (m, 1), 7.10 (m, 2). ¹³CNMR (125 MHz, CDCl₃) δ: 16.21, 35.97, 55.37, 55.59, 109.74, 126.53,130.75, 131.84, 156.84.

[0572] Intermediate 66B:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-methoxy-3-methyl-benzyl)-N-methyl-acetamide

[0573] Intermediate 66B was prepared from Intermediate 66A using MethodXVII. LC/MS (M+H) calcd for C₁₇H₂₂NO₅: 320.1; found: 320.1. HRMS (M+H)calcd for C₁₇H₂₂NO₅: 320.1498; found: 320.1490. ¹H NMR and ¹³C NMR showa mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ:1.70 (s), 1.73 (s), 2.19 (s), 2.95 (s), 2.98 (s), 3.80 (s), 3.81 (s),4.48 (s), 4.55 (s), 6.16 (s), 6.19 (s), 6.75-7.08 (overlapping m). ¹³CNMR (125 MHz, CDCl₃) δ: 16.20, 16.29, 26.80, 26.86, 33.11, 34.11, 34.94,49.94, 53.42, 55.36, 55.41, 97.40, 97.71, 109.83, 110.06, 113.63,113.74, 125.17, 126.93, 127.27, 127.46, 128.41, 129.02, 130.78, 144.43,144.51, 157.26, 157.42, 162.55, 162.67, 163.77, 164.22.

[0574] Compound 66:2-Hydroxy-3-[(4-methoxy-3-methyl-benzyl)-methyl-carbamoyl]-acrylic Acid

[0575] Compound 66 was prepared from Intermediate 66B using MethodXVIII. LC/MS calcd for C₁₄H₁₈NO₅: 280.1; found: 280.3.

EXAMPLE 67

[0576] Intermediate 67A: (4-Chloro-3-fluoro-benzyl)-methyl-amine

[0577] Intermediate 67A was prepared from 4-chloro-3-fluoro-benzaldehydeusing Method III. LC/MS (M+H) calcd for C₈H₁₀NClF; 174.0; found: 174.1.¹H NMR (500 MHz, CDCl₃) δ: 2.43 (s, 3), 3.72 (s, 2), 7.05 (m, 1), 7.15(m, 1), 7.33 (m, 1). ¹³C NMR (125 MHz, CDCl₃) δ: 35.92, 54.94, 116.08,116.25, 119.13, 119.27, 124.35, 124.38, 130.39, 141.24, 141.29, 157.12,159.10.

[0578] Intermediate 67B:N-(4-Chloro-3-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0579] Intermediate 67B was prepared from Intermediate 67A using MethodXVII. LC/MS (M+H) calcd for C₁₅H₁₆NO₄ClF: 328.1; found: 328.1. ¹H NMRand ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500MHz, CDCl₃) δ: 1.70 (s), 1.74 (s), 2.98 (s), 3.03 (s), 4.55 (s), 4.60(s), 6.08 (s), 6.17 (s), 7.08 (overlapping m), 7.34 (overlapping m). ¹³CNMR (125 MHz, CDCl₃) δ: 26.78, 26.85, 33.42, 35.46, 49.94, 53.04, 96.54,96.74, 113.91, 113.98, 114.74, 114.91, 116.15, 116.32, 120.01, 120.15,120.42, 120.55, 122.88, 122.91, 124.46, 124.49, 130.76, 131.20, 137.24,137.88, 137.93, 144.95, 145.06, 157.22, 157.47, 159.20, 159.46, 162.29,162.42, 164.10, 164.32.

[0580] Compound 67:3-[(4-Chloro-3-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0581] Compound 67 was prepared from Intermediate 67B using MethodXVIII. LC/MS calcd for C₁₂H₁₂NO₄FCl: 288.0; found: 288.1.

EXAMPLE 68

[0582] Intermediate 68A: Benzo[1,3]dioxol-5-ylmethyl-methyl-amine

[0583] Intermediate 68A was prepared frombenzo[1,3]dioxole-5-carbaldehyde using Method III. LC/MS (M+H) calcd forC₉H₁₂NO₂; 166.1; found. 166.1. ¹H NMR (500 MHz, CDCl₃) δ: 2.42 (s, 3),3.65 (s, 2), 5.95 (d, 2), 6.75-6.86 (overlapping m, 3).

[0584] Intermediate 68B:N-Benzo[1,3]dioxol-5-ylmethyl-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0585] Intermediate 68B was prepared from Intermediate 68A using MethodXVII. LC/MS (M+H) calcd for C₁₆H₁₈NO₆: 320.1; found: 320.1.

[0586] Compound 68:3-(Benzo[1,3]dioxol-5-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0587] Compound 68 was prepared from Intermediate 68B using MethodXVIII. LC/MS calcd for C₁₃H₁₄NO₆: 280.1; found: 280.1. ¹H NMR and ¹³CNMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz,CDCl₃) δ: 3.00 (s), 4.48 (s), 4.55 (s), 5.95 (s), 5.96 (s), 6.33 (s),6.39 (s), 6.61-6.79 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.51,34.70, 50.58, 53.17, 93.31, 93.44, 101.20, 101.28, 101.35, 107.13,108.36, 108.51, 108.66, 120.22, 121.59, 121.89, 129.04, 129.75, 147.35,147.56, 148.15, 148.39, 159.28, 159.36, 164.85, 170.85, 171.10.

EXAMPLE 69

[0588] Intermediate 69A:(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-methyl-amine

[0589] Intermediate 69A was prepared from2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde using Method III. LC/MS(M+H) calcd for C₉H₁₀NO₂F₂: 202.1; found: 202.1. ¹H NMR (500 MHz, CDCl₃)δ: 2.44 (s, 3), 3.73 (s, 2), 6.97-7.09 (overlapping m, 3). ¹³C NMR (125MHz, CDCl₃) δ: 35.85, 55.59, 109.05, 109.42, 123.11, 129.63, 131.66,133.68, 136.50, 142.71, 143.93.

[0590] Intermediate 69B:N-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0591] Intermediate 69B was prepared from Intermediate 69A using MethodXVII. LC/MS (M+H) calcd for C₁₆H₁₆NO₆F₂: 356.1; found: 356.1. ¹H NMRshows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃)δ: 1.70 (s), 1.74 (s), 2.97 (s), 3.01 (s), 4.56 (s), 4.60 (s), 6.11 (s),6.15 (s), 6.90-7.06 (overlapping m).

[0592] Compound 69:3-[(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylicAcid

[0593] Compound 69 was prepared from Intermediate 69B using MethodXVIII. LC/MS calcd for C₁₃H₁₂NO₆F₂: 316.1; found: 316.1. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02(s), 4.57 (s), 4.62 (s), 6.34 (s), 6.89-7.06 (overlapping m).

EXAMPLE 70

[0594] Intermediate 70A: (4-Chlorophenyl)-(4-fluorobenzyl)-amine

[0595] Intermediate 70A was prepared fromN-(4-chlorophenyl)-4-fluorobenzamide using Method II, step 2. ¹HNMR 400MHz (CDCl₃) δ (ppm): 4.28 (2H, s, NCH₂), 6.54 (2H, d, J=9 Hz,aromatics), 7.03 (2H, broad t, aromatics), 7.12 (2H, d, J=9 Hz,aromatics), 7.31 (2H, m, aromatics). MS (ESI⁺) (m/z) 236 (M+H⁺).

[0596] Intermediate 7OB:N-(4-Chloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0597] Intermediate 70B was prepared from Intermediate 70A using MethodXIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72 (6H, s, CH₃), 4.88 (2H, s,NCH₂), 5.63 (1H, s, CH), 6.94 (4H, m, aromatics), 7.19 (2H, m,aromatics), 7.32 (2H, m, aromatics). HRMS (MAB N₂) calculated forC₂₀H₁₇ClFNO₄ [M⁺]: 389. 083014: found: 389. 084846. Anal. Calcd forC₂₀H₁₇ClFNO₄: C 61.63, H 4.40, N 3.59 Found: C 61.42, H 4.45, N 3.58

[0598] Compound 70:3-[(4-Chloro-phenyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0599] Compound 70 was prepared from Intermediate 70B using MethodXVIII. HNMR 400 MHz (CDCl₃) δ (ppm): 4.89 (2H, s, NCH₂), 5.76 (1H, s,CH), 6.91 (2H, d, J=9 Hz, aromatics), 6.98 (2H, ˜t, aromatics), 7.16(2H, m, aromatics), 7.35 (2H, d, J=9 Hz, aromatics). HRMS (MAB N₂)calculated for C₁₇H₁₃ClFNO₄ [M⁺]: 349.051714: found: 349.050812.

EXAMPLE 71

[0600] Intermediate 71A:N-(4-Chloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-methyl-benzyl)-acetamide

[0601] A solution of(Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one (0.553g, 2.90 mmol) in dry dichloromethane (5 ml) was added dropwise to a cold(0-5° C.) solution of (4-chlorophenyl)-(4-methylbenzyl)-amine (0.545 g,2.35 mmol) (Ballistreri et al., J. Org. Chem., 41, 1976, 3364), pyridine(0.35 ml) and a small crystal of 4-N,N-dimethylaminopyridine in drydichloromethane (10 ml). After 30 min, the cooling bath was removed andthe resulting clear solution was stirred at 22° C. for another 30 min.The reaction mixture was then diluted wih ethyl acetate, washed withsaturated sodium bicarbonate, brine and dried (magnesium sulfate).Evaporation of the solvent in vacuo, filtration of the residue on ashort silica gel pad (elution-toluene ethyl acetate; 85:15) followed bycrystallization from ethyl acetate—hexane gave 0.794 g (87%) of thetitle amide as white needles: mp 149° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm):1.72 (6H, s, CH₃), 2.31 (3H, s, CH₃), 4.88 (2H, s, NCH₂), 5.64 (1H, s,CH), 6.93 (2H, d, J=8.5 Hz, aromatics), 7.08 (4H, m, aromatics), 7.3(2H, d, J=8.5 Hz, aromatics). Anal. Calcd for C₂₁H₂₀ClNO₄: C 65.37, H5.22, N 3.63. Found: C 65.22, H 5.25, N 3.52.

[0602] Compound 71:3-[(4-Chloro-phenyl)-(4-methyl-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0603] Compound 71 was prepared from Intermediate 71A using MethodXVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) 2.32 (3H, s, CH₃), 4.88 (2H, s,NCH₂), 5.76 (1H, s, CH), 6.92 (2H, d, J=8.6 Hz, aromatics), 7.08 (4H, m,aromatics), 7.33 (2H, d, J=8.6 Hz, aromatics). HRMS (MAB N₂) calculatedfor C₁₈H₁₆ClNO₄ [M⁺]: 345.076786: found: 345.078285.

EXAMPLE 72

[0604] Intermediate 72A:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(4-fluoro-phenyl)-acetamide

[0605] Acylation of (4-fluorobenzyl)-(4-fluorophenyl)-amine (Pombrik, S.I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 6, 1982, 1289-1294) with(Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one asdescribed in the preparation of Intermediate 71A gave the title amide asa syrup. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72 (6H, s, CH₃), 4.88 (2H, s,NCH₂), 5.29 (1H, s, CH), 6.94 (4H, m, aromatics), 7.03 (2H, m,aromatics), 7.19 (2H, m, aromatics). HRMS (MAB N₂) calculated forC₂₀H₁₇F₂NO₄ [M^(+]): 373.112565: found: 373.112320.

[0606] Compound 72:3-[(4-Fluoro-benzyl)-(4-fluoro-phenyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0607] Compound 72 was prepared from Intermediate 72A using MethodXVIII. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 4.93 (2H, s, NCH₂), 5.54 (1H, s,CH), 7.11 (2H, m, aromatics), 7.2-7.37 (6H, m, aromatics). HRMS (MAB N₂)calculated for C₁₇H₁₃F₂NO₄ [M⁺]: 333.08127: found: 333.08220.

EXAMPLE 73

[0608] Intermediate 73A:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-phenyl)-N-(4-methyl-benzyl)-acetamide

[0609] Acylation of (4-fluorophenyl)-(4-methylbenzyl)-amine (Pombrik, S.I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 10, 1981, 2406-2408) with(Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one asdescribed in the preparation of Intermediate 71A gave the title amide asa syrup. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72 (6H, s, CH₃), 2.31 (3H, s,CH₃), 4.87 (2H, s, NCH₂), 5.63 (1H, s, CH), 6.93-7.11 (8H, m,aromatics). HRMS (MAB N₂) calculated for C₂₁H₂₀FNO₄ [M⁺]: 369.137637:found: 369.137900.

[0610] Compound 73:3-[(4-Fluoro-phenyl)-(4methyl-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0611] Compound 73 was prepared from Intermediate 73A using MethodXVIII. ¹HNMR 400 MHz δ (ppm): 2.32 (3H, s, CH₃), 4. 87 (2H, s, NCH₂),5.30 (1H, s, CH), 6.96 (2H, m, aromatics), 7.0-7.2 (6H, m, aromatics).HRMS (MAB N₂) calculated for C₁₈H₁₆FNO₄ [M⁺]: 329.106336: found:329.106590, δ−0.8 ppm.

EXAMPLE 74

[0612] Intermediate 74A: N-(4-Fluorobenzyl)-furfurylamine

[0613] Intermediate 74A was prepared from 2-furoyl chloride and4-fluorobenzylamine using Method II. ¹HNMR 400 MHz (C₆D₆) δ (ppm): 3.49(2H, s, NCH₂), 3.61 (2H, s, NCH₂), 6.08 (1H, broad s, CH furyl), 6.21(1H, broad s, CH furyl), 6.92 (2H, broad t, aromatics), 7.11 (2H, m,aromatic), 7.23 (H, broad s, CH furyl). Anal. Calcd for C₁₂H₁₀FNO₂: C70.23, H 5.89, N 6.82. Found: C 70.04, H 6.03, N 6.77.

[0614] Intermediate 74B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-furan-2-ylmethyl-acetamide

[0615] Intermediate 74B was prepared from Intermediate 74A using MethodXIV. HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.74 and 1.77(6H, 2 s, CH₃), 4.43, 4.61, 4.62 and 4.64 (4H, 4 s, 2×NCH₂), 6. 14,6.21, 6.29, 6.35 and 6.37 (3H, 5 broad s, CH and CH of furyl), 7.04 (2H,m, aromatics) 7.17 (2H, m, aromatics), 7.36 and 7.4 (1H, 2 s, CH offuryl). HRMS (MAB N₂) calculated for C₁₉H₁₈FNO₅ [M⁺]: 359.116901: found:359.117325. Anal. Calcd for C₁₉H₁₈FNO₅: C 63.51, H 5.05, N 3.90. Found:C 63.87, H 5.17, N 3.74.

[0616] Compound 74:3-[(4-Fluoro-benzyl)-furan-2-ylmethyl-carbamoyl]-2-hydroxy-acrylic Acid

[0617] Compound 74 was prepared from Intermediate 74B using MethodXVIII. HNMR 400 MHz (DMSO-d₆) δ (ppm): mixture of rotamers; 4.6, 4.64,4.65 and 4.69 (4H, 4 s, 2×NCH₂), 6.18 and 6.48 (1H, 2 s, CH), 6.34-6.41(2H, m, CH of furyl), 7.13-7.32 (4H, m, aromatics), 7.59 and 7.63 (1H, 2s, CH of furyl), 13.67 (1H, broad, OH), 14.24 and 14.32 (1H, 2 broad s,OH). Anal. Calcd for C₁₆H₁₄FNO₅: C 60.19, H 4.42, N 4.39. Found: C60.15, H 4.21, N 4.30.

EXAMPLE 75

[0618] Intermediate 75A:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-furan-2-ylmethyl-N-methyl-acetamide

[0619] Intermediate 75A was prepared from N-ethylfurfuryl-amine usingMethod XIV. Solid: mp 83-86° C. (hexane) ¹HNMR 400 MHz (CDCl₃) δ (ppm):mixture of rotamers 1. 63 (6H, s, CH₃), 3 .03 and 3 .1 (3H, 2 s, NCH₃),4. 52 and 4.65 (2H, 2 s, NCH₂), 6.1-6.4 (3H, m, CH and furyl CH), 7.38and 7.4 (1H, 2 s, furyl CH). MS (ESI⁺) (m/z) 266 (M+H⁺). Anal. Calcd forC₁₃H₁₅NO₅: C 58.86, H 5.69, N 5.28. Found: C 59.02, H 5.52, N 5.12.

[0620] Compound 75:3-(Furan-2-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0621] Compound 75 was prepared from Intermediate 75A using MethodXVIII. HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.0 (3H, s,NCH₃), 4.5 and 4.7 (2H, 2 s, NCH₂), 6.3-6.6 (3H, m, CH and furyl CH),7.41 (1H, s, furyl CH). MS (ES ) (m/z) 224 (M−H)⁻. Anal. Calcd forC₁₀H₁₁NO₅: C 53.33, H 4.92, N 6.22. Found: C 53.43, H 5.0, N 5.92.

EXAMPLE 76

[0622] Intermediate 76A:N-(4-Fluorobenzyl)-3-chloro-4-methoxy-benzylamine

[0623] Intermediate 76A was prepared from 4-fluorobenzoyl chloride and3-chloro-4-methoxy-benzylamine using Method II. ¹HNMR 400 MHz (CDCl₃) δ(ppm): 3.71 (2H, s, NCH₂), 3.75 (2H, s, NCH₂), 3.89 (3H, s, OCH₃), 6.89(1H, d, J=8.2 Hz, CH), 7.02 (2H, m, aromatics), 7.2 (1H, dd, J=2.1 Hzand J=8.2 Hz, aromatic), 7.31 (2H, m , aromatics), 7.36 (1H, d, J=2.1Hz, aromatic). HRMS (MAB N₂) calculated for C₁₅H₁₅ClFNO [M^(+]):279.08262: found: 279.08157.

[0624] Intermediate 76B:N-(3-Chloro-4-methoxy-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0625] Intermediate 76B was prepared from Intermediate 76A using MethodXIV. HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.74 (6H, s,CH₃), 3.89 and 3.90 (3H, 2 s, OCH₃), 4.40, 4.46, 4.51 and 4.58 (4H, 4 s,2×NCH₂), 6.15 and 6.16 (1H, 2 S, CH), 6.84-7.27 (7H, m, aromatics). HRMS(ESI⁺) calculated for C₂₂H₂₂ClFNO₅ [M+H⁺] calculated for: 434.11707:found: 434.11820.

[0626] Compound 76:3-[(3-Chloro-4-methoxy-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0627] Compound 76 was prepared from Intermediate 76B using MethodXVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 3.90 and 3.91(3H, 2 s, OCH₃), 4.41, 4.47, 4.53 and 4.59 (4H, 4 s, 2×NCH₂), 6.39 (1H,broad s, CH), 6.87-7.25 (7H, m, aromatics). HRMS (MAB N₂) calculated forC₁₉H₁₇ClFNO₅ [M⁺]: 393.07794: found: 393.07000.

EXAMPLE 77

[0628] Intermediate 77A: (4-Fluorophenyl)-(3-pyridyl)-methanol

[0629] A solution of 3-pyridinecarboxaldehyde (5.32 g, 49.7 mmol) intetrahydrofuran (100 ml) was cooled to −78° C. and treated dropwise with25 ml (50 mmol) of a 2 M solution of 4-fluorophenyl magnesium bromide inether. The reaction mixture was then slowly warmed up to 0° C. over 1 hand then quenched by the addition of saturated aqueous sodiumbicarbonate and ethyl acetate. The organic phase was washed with brine,dried (magnesium sulfate) and concentrated under reduced pressure.Filtration of the residue on a short silica gel pad (elution ethylacetate) followed by distillation in vacuo gave 9.42 g (93%) of thetitle m aterial as a clear oil which crystallized upon standing. bp120-130° C./0.2 torr (bulb to bulb distillation, air bath temperature),mp 45-47° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 5.88 (1H, s, CH benzhydryl),7.05 (2H, m, aromatics), 7.25-7.36 (3H, m, aromatics), 7.73 (1H. d,J=7.9 Hz, aromatic), 8.44 (1H. d, J=5.2 Hz, aromatic), 8.55 (1H, s,aromatic). Anal. Calcd for C₁₂H₁₀FNO: C 70.92, H 4.96, N 6.89. Found: C70.61, H 4.86, N 6.71.

[0630] Intermediate 77B:(4-Fluorophenyl)-(3-pyridyl)-N-methyl-methylamine

[0631] A solution of Intermediate 77A (2.0 g, 9.84 mmol) in dry benzenewas treated with thionyl chloride (1.7 ml) and heated under reflux for 1h. The solvent and excess reagent were evaporated under reduce pressure.The residue was then dissolved in 60 ml of a 1.85 M solution ofmethylamine in tetrahydrofuran and the resulting mixture was heated at125° C. in a pressure vessel for 72 h. The reaction mixture was thendiluted with ethyl acetate, washed with water, brine and dried(magnesium sulfate). Evaporation of the solvent under reduce pressureand filtration of the residue on a short silica gel pad (elution ethylacetate—methanol 0-20%) followed by distillation in vacuo gave 1.38 g(64%) of the title amine as a clear oil: bp 90-100° C./0.2 torr (bulb tobulb distillation, air bath temperature). ¹HNMR 400 MHz (CDCl₃) δ (ppm):2.33 (3H, s, CH₃), 4.65 (1H, s, CH benzhydryl), 6.93 (2H, m, aromatics),7.16 (1H, dd, J=4.8 Hz and J=7.8 Hz, aromatic), 7.29 (2H, m, aromatics),7.61 (1H, m, aromatic), 8.41 (1H, broad d, aromatic), 8.56 (1H, d, J=2.1Hz, aromatic) Anal. Calcd for C₁₂H₁₀FNO. 0.2 H₂O: C 71.02, H 6.14, N12.74. Found: C 71.19, H 5.98, N 12.75.

[0632] Intermediate 77B:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[(4-fluoro-phenyl)-pyridin-3-yl-methyl]-N-methyl-acetamide

[0633] Intermediate 77C was prepared from Intermediate 77B using MethodXIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.56, 1.59 and1.69 (6H, 3 s, CH₃), 2.71 and 2.84 (3H, 2 s, NCH₃), 6.08 and 6.14 (1H, 2s, CH), 6.93-7.45 and 8.4-8.55 (8H, m, CH and aromatic). HRMS (MAB N₂)calculated for C₂₀H₁₉FN₂O₄ [M⁺]: 370.13288: found: 370.13248.

[0634] Compound 77:3-{[(4-Fluoro-phenyl)-pyridin-3-yl-methyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0635] Compound 77 was prepared from Intermediate 77B using MethodXVIII. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm) mixture of rotamers of keto(minor)—enol forms; 2.72 and 2.88 (3H, 2 s, NCH₃), 6.28 and 6.43 (1H, 2s, CH), 6.94 and 6.99 (1H, 2 s, CH), 7.25 (4H, m , aromatics), 7.42 (1H,m , aromatic), 7.60 (1H, m aromatic), 8.41 (1H, broad s , aromatic), and8.55 (1H, m, aromatic). HRMS (MAB N₂) calculated for C₂₇H₁₅FN₂O₄[M^(+]): 330.10158: found: 330.10009.

EXAMPLE 78

[0636] Intermediate 78A: 1,2-Bis-(4-fluorophenyl)-N-methyl-ethylamine

[0637] Intermediate 78A was prepared from 4,4′-difluro-deoxybenzoinusing Method III. Anal. Calcd for C₁₅H₁₅F₂N: C 72.86, H 6.11, N 5.66.Found: C 72.48, H 6.27, N 5.75. The hydrochloride salt was obtained as awhite solid; mp 155-157° C. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.39 (3H,broad s, NCH₃), 3.14 (1H, dd, J=11.0 Hz and J=13.2 Hz. CH), 3.51 (1H,dd, J=4.58 Hz and J=13.2 Hz. CH), 4.49 (1H, broad. CH), 7.03 (4H, m,aromatics), 7.22 (2H, m, aromatics), 7.50 (2H, m, aromatics).

[0638] Intermediate 78B:N-[1,2-Bis-(4-fluoro-phenyl)-ethyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0639] Intermediate 78B was prepared from Intermediate 78A using MethodXIV. MS (ESI⁺) (m/z): 402 (M+H)⁺.

[0640] Compound 78:3-{[1,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0641] Compound 78 was prepared from Intermediate 78B using MethodXVIII. MS(ESI⁻) (m/z): 360 (M−H)

EXAMPLE 79

[0642] Intermediate 79A: 4-Fluoro-3′-(N-methylcarbamoyl)-benzophenone

[0643] A solution of 3-{1-hydroxy-1-(4-fluorophenyl)-methyl}-N-methyl-benzamide (0.91 g, 3.51 mmol) in dichloromethane (75ml) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (5.9 g, 13.9 mmol) and the resulting mixture was stirred at25° C. for 18 h. The solution was then diluted with ethyl acetate,washed with 5% aqueus sodium thiosulfate, sodium bicarbonate, brine anddried (magnesium sulfate). Evaporation of the solvent under reducepressure and chromatography of the residue on silica gel (elutiontoluene-ethyl acetate, 1:1) gave 0.854 g (94%) of the title material asa white solid: mp 118-119° C. (ethyl acetate—hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.05 (3H, d, J=4.7 Hz, NCH₃), 6.29 (1H, broad, NH),7.20 (2H, m, aromatics), 7.59 (1H. t, J=8.0 Hz, aromatic), 7.84-7.3 (3H,m, aromatics), 8.05 (1H, m, aromatic), 8.14 (1H broad s, aromatic).Anal. Calcd for C₁₅H₁₂FNO₂: C 70.03, H 4.70, N 5.44. Found: C 70.04, H4.59, N 5.36.

[0644] Intermediate 79B:4-Fluoro-3′-(N-methylcarbamoyl)-benzhydrylmethylamine

[0645] Intermediate 79B was prepared using Method III from Intermediate79A. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.36 (3H, s, NCH₃), 2.95 and 2.97(3H, 2 s, NCH₃), 4.7 (1H, s. CH), 6.38 (1H, broad, NH), 6.95 (2H, m,aromatics), 7.32 (3H, m, aromatics), 7.47 (1H, broad d, aromatic), 7.60(1H, broad d, aromatic), 7.79 (1H, broad s, aromatic). MS (ESI⁺) (m/z):273 (M+H).

[0646] Intermediate 79C:3-[{[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methyl-amino}-(4-fluoro-phenyl)-methyl]-N-methyl-benzamide

[0647] Intermediate 79C was prepared from Intermediate 79B using MethodXIV. HNMR 400 MHz (DMSO-d₆) δ (ppm) mixture of rotamers; 1.48, 1.52 and1.69 (6H, 3 s, CH₃), 2.63 and 2.82 (3H, 2 s, NCH₃), 2.76 (2H, d, J=4.56Hz, CH₃), 6.19 (1H, broad s, CH benzhydryl), 6.58 and 6.96 (1H, 2 s,CH), 7.21 (4H, m, aromatics), 7.27 (1H, d, J=8.2 Hz, aromatic), 7.47(1H, t, J=7.9 Hz, aromatic), 7.64 (1H, broad s, aromatic), 7.79 (1H, d,J=8.0 Hz, aromatic) and 8.49 (1H, s, NH). HRMS (ESI+) calculated forC₂₃H₂₄FN₂O₅ [M+H⁺]: 427.16693: found: 427.16840.

[0648] Compound 79:3-{[(4-Fluoro-phenyl)-(3-methylcarbamoyl-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0649] Compound 79 was prepared from Intermediate 79C using MethodXVIII. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): mixture of rotamers; 2.70 and2.87 (3H, 2 s, NCH₃), 2.76 (2H, d, J=4.5 Hz, NCH₃), 6.31 and 6.41 (1H, 2s, CH benzhydryl), 6.76 and 6.99 (1H, 2 s, CH), 7.21 (4H, m, aromatics),7.19-7.81 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₂₀H₁₉FN₂O₅[M⁺]: 386.12780: found: 386.12843.

EXAMPLE 80

[0650] Intermediate 80A: 3,3-bis-(4-fluorophenyl)-propionic Acid EthylEster

[0651] A suspension of zinc (5.7 g, 87.2 mmol) in dichloromethane (20ml) was treated with iodine (0.1 g) and heated under reflux. A solutionof ethyl bromoacetate (10.0 g, 59.8 mmol) in dichloromethane was thenadded dropwise over 15 min and the resulting mixture was heated foranother 15 min. The thick paste was then cooled to 0-5° C. and treateddropwise with a solution of 4,4′-difluorobenzhydryl chloride (11.93 g,50.0 mmol) in dichloromethane (20 ml). The cooling bath was then removedand the mixture was stirred at 22° C. for another 2 h. The reactionmixture was quenched by the addition of 1N hydrochloric acid and ethylacetate. The organic phase was washed with water, saturated sodiumbicarbonate, brine and dried (magnesium sulfate). Evaporation of thesolvent under reduce pressure and distillation of the residue in vacuogave 11.6 g (80%) of the title material as a clear oil: bp 95-100°C./0.1 torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.14 (3H, t, J=7.1 Hz, CH₃),.3.01 (2H, d, J=8.1 Hz,CH₂), 4.06 (2H, q, J=7.1 Hz, CH₂), 4.54 (1H, t, J=8.1 Hz, CH),7.0 (4H,m, aromatics), 7.2 (4H, m, aromatics). Anal. Calcd for C₁₇H₁₆F₂O₂: C70.34, H 5.56. Found: C 70.44, H 5.50.

[0652] Intermediate 80B: 3, 3-bis-(4-fluorophenyl)-propionic Acid

[0653] Saponification of Intermediate 80A as described in thepreparation of Intermediate 1B gave the title acid as white needles: mp106-107° C. (benzene-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm)-3.05 (2H, d,J=8.1 Hz, CH₂), 4.51 (1H, t, J=8.1 Hz, CH), 7.0 (4H, m, aromatics), 7.18(4H, m, aromatics). Anal. Calcd for C₁₅H₁₂F₂O₂: C 68.69, H 4.61. Found:C 68.71, H 4.63.

[0654] Intermediate 80C: 3,3-bis-(4-Fluorophenyl)-N-methyl-propylamine

[0655] Intermediate 80C was prepared from Intermediate 80B using MethodII. ¹HNMR 400 MHz (CDCl₃) δ (ppm: 2.18 (2H, m, CH₂), 2.39 (3H, s, NCH₃),2.51 (2H, t, J=7.3 Hz, CH₂), 3.99 (1H, t, J=8.0 Hz, CH), 6.96 (4H, m,aromatics), 7.16 (4H, m, aromatics). MS (ESI⁺) (m/z): 262 (M+H).

[0656] Intermediate 80D:N-[3,3-Bis-(4-fluoro-phenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0657] Intermediate 80D was prepared from Intermediate 80C using MethodXIV. HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.67 and 1.72(6H, 2 s, CH₃), 2.29 (2H, m, CH₂), 2.97 and 3.01 (3H, 2 s, NCH₃), 3.27and 3.35 (2H, 2 m, NCH₂), 3.87 and 3.92 (1H, 2 t, J=7.98 and J=7.83 Hz,CH), 5.85 and 6.07 (1H, 2 s, CH), 6.98 (4H, m, aromatics) and 7.17 (4H,m, aromatics). HRMS (ESI⁺) calculated for C₂₃H₂₄F₂NO₄ [M+H⁺]: 416.16733:found: 416.16850.

[0658] Compound 80:3-{[3,3-Bis-(4-fluoro-phenyl)-propyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0659] Compound 80 was prepared from Intermediate 80D using MethodXVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.29 (2H, m,CH₂), 3.0 (3H, s, NCH₃), 3.29 and 3.39 (2H, 2 m, NCH₂), 3.88 and 3.91(1H, 2 t, J=7.7 and J=8.2 Hz, CH), 6.01 and 6.24 (1H, 2 s, CH), 7.08(4H, m, aromatics) and 7.19 (4H, m, aromatics). HRMS (MAB N₂) calculatedfor C₂₀H₁₉F₂NO₄ [M⁺]: 375.12821: found: 375.12874.

EXAMPLE 81

[0660] Intermediate 81A:2-{1-Hydroxy-1-(4-fluorophenyl)-methyl}-N-methyl-benzamide

[0661] Reaction of 2-bromo-N-methylbenzamide with 4-fluorobenzaldehydeas described in the preparation of

[0662] Intermediate 2A gave the title material as a white solid: mp:133-134° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm) 2.81 (3H, d, J=5.1 Hz, NCH₃),5.89 (2H, broad s, CH and NH), 7.01 (2H, m, aromatics), 7.28-7.45 (6H,m, aromatics). Anal. Calcd for C₁₅H₁₄FNO₂: C 69.49, H 5.44, N 5.40.Found: C 69.46, H 5.44, N 5.41.

[0663] Intermediate 81B: 2-(4-Fluorobenzyl)-N-methyl-benzamide

[0664] Hydrogenolysis of Intermediate 81A, as described in thepreparation of Intermediate 2B, gave the title amide as white needles:mp 129-130° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.9 (3H, d, J=4.5 Hz,NCH₃), 4.16 (2H, s, CH₂), 5.61 (1H, broad, NH), 6.96 (2H, m, aromatics),6.99-7.38 (6H, m, aromatics). Anal. Calcd for C₁₅H₁₄FNO: C 74.06, H5.80, N 5.76. Found: C 74.08, H 5.86, N 5.69.

[0665] Intermediate 81D: 2-(4-Fluorobenzyl)-N-methyl-benzylamine

[0666] Reduction of Intermediate 81C, as described in the preparation ofIntermediate 8B, gave the title amine as an oil: bp 85-90° C./0.1 torr(bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (C₆D₆)δ (ppm): 2.26 (3H, s, NCH₃), 3.54 (2H, s, CH₂), 4.0 (2H, s, CH₂), 6.87(2H, m, aromatics), 6.94 (2H, m, aromatics), 7.07 (1H, d, aromatic),7.23 (2H, m aromatics),7.4 (1H, d, aromatic). MS (ESI⁺) (m/z) 230 (M+H).Anal. Calcd for C₁₅H₁₆FN: C 78.57, H 7.03, N 6.10. Found: C 78.37, H7.00, N 6.16.

[0667] Intermediate 81E:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[2-(4-fluoro-benzyl)-benzyl]-N-methyl-acetamide

[0668] Intermediate 81E was prepared from Intermediate 81D using MethodXIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm: mixture of rotamers; 1.59 and 1.72(6H, 2 s, CH₃), 2.81 and 2.92 (3H, 2 s, NCH₃), 3.96 and 3.99 (2H, 2 s,CH₂), 4.43 and 4.64 (2H, 2 s, NCH₂), 5.88 and 6.03 (2H, 2 s, CH),6.91-7.3 (8H, m, aromatics). HRMS (MAB N₂) calculated f or C₂₂H₂₂FNO₄[M^(+]): 383.15329: found: 383.15425.

[0669] Compound 81: 3-{[2-(4-Fluoro-benzyl)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0670] Compound 81 was prepared from Intermediate 81E using MethodXVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.80 and 2.94(3H, 2 s, NCH₃), 3.98 and 3.99 (2H, 2 s, CH₂), 4.44 and 4.64 (2H, 2 s,NCH₂), 6.06 and 6.19 (H, 2 s, CH), 6.90-7.36 (8H, m, aromatics). HRMS(MAB N₂) calculated for C₁₉H₁₈FNO₄ [M⁺]: 343.12199: found: 343.12171.

EXAMPLE 82

[0671] Intermediate 82A: 2-(4-Fluorobenzyloxy)-N-methyl-benzylamine

[0672] Intermediate 82A was prepared from2-(4-fluorobenzyloxy)-benzaldehyde (Hellwinkle et al using Method III.Synthesis 1995, 1135.). ¹HNMR 400 MHz (C₆D₆) δ (ppm): 1.90 (3H, s,NCH₃), 3.56 (2H, s, NCH₂), 4.77 (2H, s, OCH₂), 6.50 (1H, d, J=7.6 Hz,aromatic), 6.73 (1H, broad t, aromatic), 6.83 (2H, m, aromatics), 6.95(1H, broad t, aromatic), 7.28 (2H, m, aromatics), 7.47 (1H, d, J=7.7 Hz,aromatic). HRMS (MAB N₂) calculated for C₁₅H₁₆FNO [M^(+]): 245.12159:found: 245.12192, δ −1.3 ppm.

[0673] Intermediate 82B:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[2-(4-fluoro-benzyloxy)-benzyl]-N-methyl-acetamide

[0674] Intermediate 82B was prepared from Intermediate 82A using MethodXIV. HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.67 and 1.73(6H, 2 s, CH₃), 2.98 and 3.01 (3H, 2 s, NCH₃), 4.57 and 4.72 (2H, 2 s,NCH₂), 5.04 (2H, s, OCH₂), 6.1 and 6.16 (H, 2 s, CH), 6.91-7.41 (8H, m,aromatics). HRMS (MAB N₂) calculated for C₂₂H₂₂FNO₅ [M^(+]): 399.1482:found: 399.1499.

[0675] Compound 82:3-{[2-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylicAcid

[0676] Compound 82 was prepared from Intermediate 82B using MethodXVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.0 and 3.01(3H, 2 s, NCH₃), 4.58 and 4.72 (2H, 2 s, NCH₂), 5.03 (2H, s, OCH₂), 6.30and 6.32 (H, 2 s, CH), 6.95-7.52 (8H, m, aromatics). HRMS (MAB N₂)calculated for Cl₉H₁₈FNO₅ [M^(+]): 359.1169: found: 359.1165.

EXAMPLE 83

[0677] Intermediate 83A: (4-chlorobenzyl)-(3,4-dichlorobenzyl)-amine

[0678] Intermediate 83A was prepared fromN-(4-chlorobenzyl)-3,4-dichlorobenzamide (Borgma et al. Farmaco Ed. Sci.1977, 32, 813) using Method II, step 2. ¹HNMR 400 MHz (C₆D₆) δ (ppm):3.22 (2H, s, NCH₂), 3.31 (2H, s, NCH₂), 6.78 (1H, d, J=8.5 Hz,aromatic), 6.99 (2H, d, J=8.1 Hz, aromatics), 7.15 (2H, d, J=8.1 Hz,aromatics), 7.24-7.31 (3H, m, aromatics).

[0679] Intermediate 83B:N-(4-Chloro-benzyl)-N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide

[0680] Intermediate 83B was prepared from Intermediate 83A using MethodXIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.77 (6H, s,CH₃), 4.47, 4.51, 4.57 and 4.6 (4H, 4 s, 2×NCH₂), 6.12 and 6.17 (1H, 2s, CH), 7.02-7.47 (7H, m, aromatics). HRMS (FAB calculated forC₂₁H₁₉Cl₃NO₄ [M+H⁺]: 454.03796 found: 454.03740.

[0681] Compound 83:3-[(4-Chloro-benzyl)-(3,4-dichloro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0682] Compound 83 was prepared from Intermediate 83B using MethodXVIII. Solid: mp 152° C. (dec. (hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm):mixture of rotamers; 4.48, 4.51, 4.59 and 4.63 (4H, 4 s, 2×NCH₂), 6.35and 6.41 (1H, 2 s, CH), 7.08-7.48 (7H, m, aromatics).

[0683] HRMS (FAB ) calculated for C₁₈H₁₅Cl₃NO₄ [M+H⁺]: 414.00665: found:414.00820.

EXAMPLE 84

[0684] Intermediate 84A: 2-Benzyl-N-methyl-benzylamine

[0685] Intermediate 84A was prepared using Method II, step 2 fromIntermediate 81B. ¹HNMR 400 MHz (C₆D₆) δ (ppm) : 2.27 (3H, s, NCH₃), 3.6(2H, s, CH₂), 4.13 (2H, s, CH₂), 7.14-7.45 (8H, m, aromatics). MS (ESI⁺)(m/z): 212 (M+H). Hydrochloride salt: Anal. Calcd for C₁₅H₁₆FN. HCl: C72.72, H 7.32, N 5.65. Found: C 72.71, H 7.26, N 5.64.

[0686] Intermediate 84B: N-(2-Benzyl-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0687] Intermediate 84B was prepared from Intermediate 84A using MethodXIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.67 and 1.74(6H, 2 s, CH₃), 2.78 and 2.93 (3H, 2 s, NCH₃), 4.03 and 4.06 (2H, 2 s,CH₂), 4.47 and 4.69 (2H, 2 s, NCH₂), 5.93 and 5.99 (H, 2 s, CH ),7.09-7.34 (8H, m, aromatics). MS (ESI⁺) (m/z) 366 (M+H⁺)

[0688] Compound 84:3-[(2-Benzyl-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0689] Compound 84 was prepared from Intermediate 84B using MethodXVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.78 and 2.94(3H, 2 s, NCH₃), 4.05 and 4.06 (2H, 2 s, CH₂), 4.48 and 4.68 (2H, 2 s,NCH₂), 6.11 and 6.18 (H, 2 s, CH ), 7.04-7.37 (8H, m, aromatics). HRMS(MAB N₂) calculated for C₁₉H₁₉NO₄ [M⁺]: 325.131408: found: 325.130098.

EXAMPLE 85

[0690] Intermediate 85A:N-(3-Biphenyl-4-yl-propyl)-N-(4-fluoro-benzyl)-acetamide

[0691] Intermediate 85A was prepared from(3-biphenyl-4-ylpropyl)-(4-fluorobenzyl)-amine hydrochloride usingMethod IV. ¹H NMR shows a mixture of rotamers at room temperature. ¹HNMR (CDCl₃) δ: 1.90 (m), 2.10 (s), 2.11 (s), 2.65 (m), 3.21 (m), 3.42(m), 4.46 (s), 4.54 (s), 6.95-7.60 (overlapping m).

[0692] Compound 85:3-[(3-Biphenyl-4-yl-propyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0693] Compound 85 was prepared from Intermediate 85A using Method XII.MS (M−H) calcd for C₂₆H₂₃NO₄F: 432.16; found: 432.11. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.99(m), 2.66 (m), 3.26 (m), 3.47 (m), 3.76 (m), 4.48 (s), 4.57 (s), 6.30(s), 6.33 (s), 6.96-7.61 (overlapping m).

EXAMPLE 86

[0694] Intermediate 86A:N-(4-Fluoro-benzyl)-N-(2-pyridin-4-yl-ethyl)-acetamide

[0695] Intermediate 86A was prepared from N-(2-pyridin-4-yl-ethyl)-acetamide and 4-fluorobenzylbromide using Method VII. ¹HNMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz,d₆-MeOD) δ: 2.03 (s), 2.12 (s), 2.87 (t, J=8), 2.93 (t, J=8), 3.59 (m),4.56 (s), 4.60 (s), 7.06 (m), 7.23-7.31 (overlapping m), 8.40 (m), 8.44(m).

[0696] Compound 86:3-[(4-Fluoro-benzyl)-(2-pyridin-4-yl-ethyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0697] Compound 86 was prepared from Intermediate 86A using Method XII.MS (M−H calcd for C₁₈H₁₆N₂O₄F: 343.11; found: 343.06. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ:3.19 (m), 3.83 (m), 4.71 (s), 6.08 (s), 6.30 (s), 7.05 (m), 7.29 (m),7.35 (m), 7.95 (m), 8.72 (m).

EXAMPLE 87

[0698] Intermediate 87A:N-[3-(2-Chloro-phenyl)-propyl]-N-(4-fluoro-benzyl)-acetamide

[0699] Intermediate 87A was prepared from[3-(2-chloro-phenyl)-propyl]-(4-fluoro-benzyl)-amine hydrochloride usingMethod IV. ¹H NMR shows a mixture of rotamers at room temperature. ¹HNMR (500 MHz, CDCl₃) δ: 1.86 (m), 2.12 (s), 2.70 (m), 3.23 (m), 3.42(m), 4.48 (s), 4.54 (s), 6.95-7.36 (overlapping m).

[0700] Compound 87:3-[[3-(2-Chloro-phenyl)-propyl]-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0701] Compound 87 was prepared from Intermediate 87A using Method XII.MS (M−H) calcd for C₂₀H₁₈NO₄ClF: 390.04; found: 390.07. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (300 MHz, d₆-MeOD) δ:1.87 (m), 2.72 (m), 3.36 (m), 3.50 (m), 4.63 (s), 6.25 (s), 6.31 (s),6.92-7.36 (overlapping m).

EXAMPLE 88

[0702] Intermediate 88A:N-(4-Fluoro-benzyl)-N-[2-(4-fluoro-benzyloxy)-phenyl]-acetamide

[0703] Intermediate 88A was prepared from2-(4-fluoro-benzyloxy)-phenylamine and 4-fluorobenzylbromide the samemethod used for Intermediate 43A. ¹H NMR (500 MHz, CDCl₃) δ: 1.83 (s,3), 4.46 (d, 1, J=14), 4.90 (dd, 2, J=12, 60), 5.01 (d, 1, J=14).6.59-7.25 (overlapping m, 12).

[0704] Intermediate 88B:3-{(4-Fluoro-benzyl)-[2-(4-fluoro-benzyloxy)-phenyl]-carbamoyl}-2-hydroxy-acrylicAcid Methyl Ester

[0705] Intermediate 88B was prepared from intermediate 88A using MethodIX. MS (M−H) calcd for C₂₅H₁₉F₃NO₅: 470.1; found: 470.1 ¹H NMR (500 MHz,CDCl₃) δ: 3.80 (S, 3), 4.48 (d, 1, J=14), 4.93 (dd, 2, J=12, 33), 5.12(d, 1, J=14), 5.64 (s, 1), 6.60-7.22 (overlapping m, 12).

[0706] Compound 88:3-{(4-Fluoro-benzyl)-[4-fluoro-2-(4-fluoro-benzyloxy)-phenyl]-carbamoyl}-2-hydroxy-acrylicAcid

[0707] Compound 88 was prepared from Intermediate 88B using Method XII.MS (M−H) calcd for C₂₄H₁₇NO₄F₃: 456.11; found: 456.00. ¹H NMR (500 MHz,CDCl₃) δ: 4.50 (d, J=14), 4.89 (d, J=12), 4.95 (d, J=12), 5.09 (d,J=14), 5.73 (s), 6.61-7.21 (m).

EXAMPLE 89

[0708] Intermediate 89A:N-(3,5-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)N-methylacetamide

[0709] Coupling of(Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one withN-methyl-3,5-dichlorobenzylamine (Meindl, W. R. et al., J. Med. Chem.,27, 1984, 1111-1118) as described in Method XIV gave the title materialas a syrup. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.71 and1.75 (6H, 2 s, CH₃), 2.98 and 3.04 (3H, 2 s, NCH₃), 4.54 and 4.60 (2H, 2s, NCH₂), 6.08 and 6.18 (1H, 2 s, CH) 7.07-7.31 (3H, m, aromatics). HRMS(MAB N₂) calculated for C₁₅H₁₅Cl₂NO₄ [M⁺]: 343.037814: found:343.038563.

[0710] Compound 89:3-[(3,5-dichloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0711] Saponification of Intermediate 89A carried out using Method XVIIIyielded the title acid as a white solid. ¹HNMR 400 MHz (DMSO-d₆) δ(ppm): mixture of rotamers; 3.06 (3H, s, NCH₃), 4.55 and 4.61 (2H, 2 s,NCH₂), 6.31 and 6.39 (1H, 2 s, CH), 7.05-7.34 (3H, m, aromatics). HRMS(MAB N₂) calculated f or C₁₂H₂₂Cl₂NO₄ [M⁺]: 303.006513: found:303.007587.

EXAMPLE 90

[0712] Intermediate 90A: N-(3,4-Dichlorophenyl)-4-fluorobenzamide

[0713] Reaction of 4-fluorobenzoyl chloride with 3,4-dichloroanilineusing Method II, step 1, gave the title amide as crystals: mp 160-161°C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 7.19 (2H, m,aromatics), 7.44 (2H, m, aromatics), 7.70 (1H, broad, NH), 7.88 (3H, m,aromatics). Anal. Calcd for C₁₃H₁₈Cl₂FNO: C 54.96, H 2.84, N 4.93.Found: C 54.96, H 2.87, N 4.90.

[0714] Intermediate 90B: (3,4-Dichlorophenyl)-(4-fluorobenzyl)-amine

[0715] Reduction of Intermediate 90A using Method II step 2, gave thetitle amine. The hydrochloride salt was obtained as a white solid. ¹HNMR400 MHz (DMSO-d₆) δ (ppm): 4.25 (2H, s, NCH₂), 6.56 (1H, dd, J=2.6 Hzand J=8.7 Hz, aromatic), 6.73 (1H, d, J=2.6 Hz, aromatic), 7.15 (2H, m,aromatics), 7.22 (1H, d, J=8.7 Hz, aromatic), 7.36 (2H, m, aromatics).

[0716] Intermediate 90C:N-(3,4-dichloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0717] Acylation of Intermediate 90B with(Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one asdescribed in Method XIV gave the title amide as a foam. ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.73 (6H, s, CH₃), 4.88 (2H, s, NCH₂)₁ 5.63 (1H, s,CH), 6.81 (1H, dd, J=2.7 Hz and J=8.5 Hz, aromatic), 6.97 (2H, m,aromatics), 7.15 (1H, d, J=2.7 Hz, aromatic), 7.19 (2H, m, aromatics),7.41 (1H, d, J=8.5 Hz, aromatic). HRMS (FAB) calculated forC₂₀H₁₇Cl₂FNO₄ [M+H⁺]: 424.05188: found: 424.05120.

[0718] Compound 90:3-[(3,4-dichloro-phenyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicAcid

[0719] Saponification of Intermediate 90C carried out using Method XVIIIyielded the title acid as a white solid. ¹HNMR 400 MHz (DMSO-d₆) δ(ppm): 4.97 (2H, s, NCH₂), 5.75 (1H, broad s, CH), 7.12 (2H, m,aromatics), 7.2 (1H, dd, aromatic), 7.27 (2H, m, aromatics), 7.69 (1H,d, J=8.6 Hz, aromatic), 7.71 (1H, d, J=2.4 Hz, aromatic). HRMS (MAB N₂ )calculated for C₁₇H₁₂Cl₂FNO₄ [M⁺]: 383.012742: found. 383.012742.

EXAMPLE 91

[0720] Intermediate 91A:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-4-methyl-benzyl)-acetamide

[0721] Intermediate 91A was prepared 3-fluoro-4-methyl-benzyl-aminehydrochloride using Method XVII HRMS (M+H) calcd for C₁₅H₁₇NO₄F:294.1142; found: 294.1146. ¹H NMR (500 MHz, CDCl₃) δ: 1.73 (s, 6), 2.25(s, 3), 4.49 (s, 1), 4.50 (s, 1) 5.90 (s, 1), 6.69 (br s, 1), 6.96 (m,2), 7.13 (m, 1). ¹³C NMR (125 MHz, CDCl₃) δ: 14.29, 26.86, 29.52, 42.84,67.10, 101.21, 107.65, 113.97, 114.05, 114.23, 122.90, 122.93, 123.94,124.07, 131.65, 131.69, 137.77, 143.05, 160.41, 161.66, 162.35, 163.07.

[0722] Compound 91:3-(3-Fluoro-4-methyl-benzylcarbamoyl)-2-hydroxy-acrylic Acid

[0723] Compound 91 was prepared from Intermediate 91A using MethodXVIII. HRMS (M−H) calcd for C₁₂H₁₁NO₄F: 252.0672; found: 252.0676. ¹HNMR (500 MHz, DMSO) δ: 2.20 (s, 3), 4.36 (m, 2), 6.04 (s, 1), 7.03 (m,2), 7.25 (m, 1), 9.01 (m, 1). ¹³C NMR (125 MHz, DMSO) δ: 13.72, 13.74,41.17, 97.80, 113.63, 113.81, 122.65, 122.77, 123.01, 131.47, 131.51,138.31, 138.37, 157.52, 159.50, 161.43, 163.31, 170.32.

EXAMPLE 92

[0724] Intermediate 92A :N-[Bis-(4-chloro-phenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide

[0725] Intermediate 92A was prepared fromBis-(4-chloro-phenyl)-methyl-amine hydrochloride using Method XIV. ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.75, (6H, s, CH₃), 5.93 (1H, s, CH), 6.29 (1H,d, J=8.2 Hz, CH benzhydryl), 6.75 (1H, broad d, NH), 7.18 (4H, broad d,aromatics), 7.34 (4H, broad d, aromatics). HRMS (MAB N₂) calculated forC₂₀H₁₇Cl₂NO₄ [M^(+]): 405.05364: found: 405.05432.

[0726] Compound 92:3-{[Bis-(4-chloro-phenyl)-methyl]-carbamoyl}-2-hydroxy-acrylic Acid

[0727] Compound 92 was prepared from Intermediate 92A using MethodXVIII. HNMR 400 MHz (DMSO-d₆) δ (ppm): 6.16 (1H, s, CH), 6.23 (1H, d,J=8.7 Hz, CH benzhydryl), 7.32 (4H, broad d, aromatics), 7.44 (4H, broadd, aromatics), 9.44 (1H, d, J 8.7 Hz, NH). HRMS (MAB N₂) calculated forC₁₇H₁₃Cl₂NO₄ [M^(+]): 365.02216: found: 365.02317.

[0728] Chemical intermediates of the present invention, having thefollowing formula, were prepared according to Method XV.

HPLC Retention Intermediate time MS Data Number Q (min) Formula (M + H)⁺ 93A

1.86 C₁₅H₁₇NO₄ 276  94A

1.83 C₁₅H₁₇NO₅ 292  95A

1.88 C₁₅H₁₇NO₄ 276  96A

1.76 C₁₅H₁₇NO₅ 292  97A

1.92 C₁₅H₁₇NO₄ 276  98A

1.81 C₁₄H₁₄FNO₄ 280  99A

1.99 C₁₄H₁₄Cl NO₄ 296 100A

1.74 C₁₅H₁₇NO₅ 292 101A

1.93 C₁₅H₁₇NO₄ 276 102A

2.12 C₁₅H₁₄F₃NO₄ 330 103A

1.77 C₁₄H₁₄N₂O₆ 307 104A

1.98 C₁₄H₁₄Cl 296 105A

2.34 C₁₈H₂₃NO₄ 318 106A

1.91 C₁₅H₁₆FN O₄ 294 107A

2.12 C₁₄H₁₃Cl₂NO₄ 330 108A

1.84 C₁₆H₁₉NO₆ 322 109A

1.91 C₁₄H₁₃F₂NO₄ 298 110A

1.85 C₁₅H₁₇NO₄ 276 111A

1.85 C₁₅H₁₇NO₄ 276 112A

1.86 C₂₀H₁₉NO₄ 338 113A

1.91 C₂₁H₂₁NO₄ 352 114A

1.99 C₁₆H₁₉NO₄ 290 115A

1.88 C₁₈H₂₃NO₄ 318 116A

1.82 C₁₅H₁₅Cl₂NO₄ 344 117A

1.95 C₂₂H₂₃NO₄ 366 118A

1.77 C₁₆H₁₈Cl NO₅ 340 119A

1.64 C₁₆H₁₉NO₄ 290 120A

2.09 C₂₃H₂₅NO₄ 380 121A

1.64 C₁₆H₁₉NO₄ 290 122A

2.18 C₂₄H₂₅Cl₂NO₄ 462 123A

2.01 C₂₂H₂₂FN O₄ 384 124A

1.95 C₂₀H₂₇NO₅ 362 125A

2.06 C₂₃H₂₄Cl NO₅ 430 126A

1.53 C₂₁H₂₈N₂O₇ 421 127A

2.71 C₂₄H₂₇NO₅ 410 128A

2.29 C₂₄H₂₇NO₆ 426 129A

1.95 C₁₆H₁₉NO₄ 290 130A

2.53 C₂₁H₃₀N₂O₄ 375 131A

1.47 C₁₅H₁₈N₂O₄ 291 132A

1.71 C₁₈H₂₃NO₆ 350 133A

2.39 C₂₃H₂₇NO₆ 414 134A

2.15 C₁₈H₂₃NO₅ 334 135A

2.46 C₂₂H₂₉NO₆ 404 136A

2.62 C₂₆H₂₇NO₄ 418 137A

2.36 C₁₈H₂₃NO₄ 318 138A

2.15 C₂₀H₂₆N₂O₅ 375 139A

2.22 C₁₉H₁₉NO₄ 326 140A

1.74 C₁₉H₂₅NO₆ 364 141A

2.63 C₂₅H₂₈N₂O₄ 421 142A

2.89 C₃₀H₃₁NO₄ 470 143A

3.9  C₂₆H₃₀FN O₄ 440

[0729] Compounds of the present invention, as shown in the followingformula, were prepared according to Method XIX.

Compound MS Data Number Q Formula (M − H)⁻  93

C₁₂H₁₃NO₄ 234  94

C₁₂H₁₃NO₅ 250  95

C₁₂H₁₃NO₄ 234  96

C₁₂H₁₃NO₅ 250  97

C₁₂H₁₃NO₄ 234  98

C₁₁H₁₀FNO₄ 238  99

C₁₁H₁₀ClNO₄ 254 100

C₁₂H₁₃NO₅ 250 101

C₁₂H₁₃NO₄ 234 102

C₁₂H₁₀F₃NO₄ 288 103

C₁₁H₁₀N₂O₆ 265 104

C₁₁H₁₀ClNO₄ 254 105

C₁₅H₁₉NO₄ 276 106

C₁₂H₁₂FNO₄ 252 107

C₁₁H₉Cl₂NO₄ 288 108

C₁₃H₁₅NO₆ 280 109

C₁₁H₉F₂NO₄ 256 110

C₁₂H₁₃NO₄ 234 111

C₁₂H₁₃NO₄ 234 112

C₁₇H₁₅NO₄ 296 113

C₁₈H₁₇NO₄ 310 114

C₁₃H₁₅NO₄ 248 115

C₁₅H₁₉NO₄ 276 116

C₁₂H₁₁Cl₂NO₄ 302 117

C₁₉H₁₉NO₄ 324 118

C₁₃H₁₄ClNO₅ 298 119

C₁₃H₁₅NO₄ 248 120

C₂₀H₂₁NO₄ 338 121

C₁₃H₁₅NO₄ 248 122

C₂₁H₂₁Cl₂NO₄ 420 123

C₁₉H₁₈FNO₄ 342 124

C₁₇H₂₃NO₅ 320 125

C₂₀H₂₀ClNO₅ 388 126

C₁₈H₂₄N₂O₇ 379 127

C₂₁H₂₃NO₅ 368 128

C₂₁H₂₃NO₆ 384 129

C₁₃H₁₅NO₄ 248 130

C₁₈H₂₆N₂O₄ 333 131

C₁₂H₁₄N₂O₄ 249 132

C₁₅H₁₉NO₆ 308 133

C₂₀H₂₃NO₆ 372 134

C₁₅H₁₉NO₅ 292 135

C₁₉H₂₅NO₆ 362 136

C₂₃H₂₃NO₄ 376 137

C₁₅H₁₉NO₄ 276 138

C₁₇H₂₂N₂O₅ 333 139

C₁₆H₁₅NO₄ 284 140

C₁₆H₂₁NO₆ 322 141

C₂₂H₂₄N₂O₄ 379 142

C₂₇H₂₇NO₄ 428 143

C₂₃H₂₆NO₄ 398

EXAMPLE 144

[0730] Compound 144: 2-Hydroxy-but-2-enedioic acid4-[bis-(4-fluoro-benzyl)-amide]1-propylamide

[0731] Compound 144 was prepared from Compound 11 using Method XX. MS(M−H) calcd for C₂₁H₂₁N₂O₃F₂: 387.15; found: 387.11. ¹H NMR (500 MHz,d₆-MeOD) δ: 0.92 (t, 3, J=7), 1.58 (sextet, 2, J=7), 3.24 (q, 2, J=7),4.59 (s, 2), 4.63 (s, 2), 6.32 (s, 1), 7.05 (m, 4), 7.20 (m, 2), 7.28(m, 2).

EXAMPLE 145

[0732] Compound 145:{3-[Bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acryloylamino}-aceticAcid

[0733] Compound 145 was prepared from Compound 11 using Method XX. MS(M−H) calcd for C₂₀H₁₇N₂O₅F₂: 403.11; found: 403.12. ¹H NMR (500 MHz,d₆-MeOD) δ: 4.00 (s, 2), 4.60 (s, 20, 4.64 (s, 2), 6.36 (s, 1), 7.05 (m,4), 7.20 (m, 2), 7.29 (m, 2).

EXAMPLE 146

[0734] Compound 146: 2-Hydroxy-but-2-enedioic acid1-[(6-benzenesulfonylamino-6-oxo-hexyl)-amide]4-[bis-(4-fluoro-benzyl)-amide]

[0735] Compound 146 was prepared from Compound 11 using Method XX. MS(M−H) calcd for C₃₀H₃₀N₃O₆SF₂: 598.18; found: 598.05. ¹H NMR (500 MHz,DMSO) δ: 1.07 (m, 2), 1.36 (m, 4), 2.18 (t, 2, J=7), 3.06 (m, 2), 4.62(s, 2), 4.66 (s, 2), 6.15 (s), 7.12-8.506 (overlapping m).

EXAMPLE 147

[0736] Compound 147: 2-Hydroxy-but-2-enedioic acid1-[(6-benzenesulfonylamino-6-oxo-hexyl)-amide]4-[[3-(2-chloro-phenyl)-propyl]-(4-fluoro-benzyl)-amide]

[0737] Compound 147 was prepared from Compound 87 using Method XX. MS(M−H) calcd for C₃₂H₃₄N₃O₆SClF: 642.18; found: 642.08. ¹H NMR shows amixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.27(m), 1.50 (m), 1.61 (m), 1.89 (m), 2.27 (m), 2.72 (m), 3.26-3.46(overlapping m), 4.60 (s), 6.40 (s), 6.43 (s), 6.96-8.05 (overlappingm).

[0738] Biological Activity

[0739] The in vitro activities, against integrase, of compounds of thepresent invention were measured by one of the following three methods.

[0740] Method A:

[0741] In Method A, the in vitro activity against integrase was measuredin a manner which was similar to previously disclosed methods (cf.Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock, K.;Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.;Miller, M. D. Science, 2000, 287, 646) Purified recombinant HIV-1integrase was incubated with immobilized precleaved substrate DNA in a96 well plate for 20 min at 37° C. After the integration complex wasformed, compounds at desired concentrations were added to the wellsfollowed by a 10 min incubation at 37° C. Biotinyted Target DNA was thenadded and the reaction was carried out for an additional 1 hour at 37°C. Wells were then washed thoroughly to remove any free DNA andintegration activity was measured by using a commercial kit toquantitate the amount of biotinyted target DNA integrated into thesubstrate.

[0742] Method B (SPA Assay):

[0743] In Method B, the in vitro activity against integrase was measuredby binding, for each reaction, 5 pmole of biotin labeled substrate DNAto 100 ug of Streptavidin coated PVT SPA beads (Amersham PharmaciaBiotech). 0.26 ng of recombinant integrase was then incubated with thebeads for 90 min at 37° C. Unbound enzyme was removed by washing thecomplex followed by addition of inhibitors and 0.1 fmol of P33 labeledtarget DNA. Reaction was stopped by adding EDTA to a final concentrationof 10 mM. Samples were counted in TopCountNXT (Packard) and the CPM wasused as a measure of integration. Reaction condition was as described inA. Engelman and R. Craigie , J. Virol. 69, 5908-5911 (1995). Thesequences of substrate and target DNA were described in Nucleic AcidResearch 22, 1122 (1994).

[0744] Method C (Electroluminesence Assay):

[0745] The ECL assay of Method C is essentially the same as the SPAassay of Method B, except that 0.5 μg of Streptavidin coated magneticbeads and 0.5 pmol Ru labeled target DNA were used for each reactioninstead of SPA beads and P33 labeled DNA. The samples were read in a M8analyzer (IGEN International, Inc). Percent inhibition of Compound HIVIntegrase Assay Number at 70 uM Method  1 40 A  2 88 A  3 99 A  4 90 A 5 65 A  6 75 A  7 32 A 10 79 A 11 97 B 12 85 A 13 94 A 14 94.5 B 15 97A 16 97 B 17 89.5 A 18 89.5 A 19 96.5 A 20 97.5 A 21 98 A 22 75 A 23 55A 24 90 A 25 96.5 A 26 97 A 27 33.5 A 28 96.5 A 29 38 A 30 84 A 31 82 A32 93 A 33 90 A 34 85 A 35 95.5 A 36 30 A 37 82.5 A 38 70 A 39 85 A 4090 A 41 95 A 42 91 A 43 93.5 A 44 95.5 C 45 99 C 46 99 C 47 99 C 48 99 C49 99 C 50 99 C 51 100 C 52 99 C 53 99 B 54 99 B 55 99 B 56 88 B 57 99 B58 99 B 59 98 B 60 99 B 61 99 B 62 99 B 63 98 B 64 95 B 70 92 B 71 99 B72 99 B 73 99 B 74 98 B 75 91 C 76 99 B 77 60 A 78 75 C 79 90 C 80 90 B81 95 B 82 80 A 84 88 B 85 94 C 86 97 C 87 99 C 88 90 A 91 99 B 92 94 B94 55 B 95 45 B 96 65 B 97 70 B 98 80 B 99 80 B 100  70 B 101  80 B 102 60 B 103  80 B 104  83 B 105  35 B 106  40 B 107  80 B 108  65 B 109  60B 111  25 B 112  99 B 114  97 B 115  97 B 116  100 B 117  68 B 118  85 B119  40 B 120  97 B 121  95 B 123  98 B 125  75 B 144  83 C 145  95 A146  98 B 147  98 C

We claim:
 1. A compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ isH, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substitutedwith 1-3 R⁵; d) R⁴ is carbocylic radical, heterocyclic radical, aryloxy,aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ isoptionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl ornaphthalen-1-yl; e) each R⁵ is independently selected from H, halo,C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl,R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ isH, halo; g) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylenegroup; h) B¹ is selected from the group consisting of

i) R⁷ is H or C₁-C₄ alkyl, or a pharmaceutically acceptable salt orsolvate thereof.
 2. A compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ isH, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substitutedwith 1-3 R⁵; d) R⁴ is carbocylic radical, heterocyclic radical, aryloxy,aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ isoptionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl ornaphthalen-1-yl; e) each R⁵ is independently selected from H, halo,C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl,R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ isH, halo; g) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylenegroup; h) B¹ is selected from the group consisting of

i) R⁷is H or C₁-C₄ alkyl, or a pharmaceutically acceptable salt, solvateor prodrug thereof.
 3. A prodrug of claim 2 having the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ isH, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substitutedwith 1-3 R⁵; d) R⁴ is carbocylic radical, heterocyclic radical, aryloxy,aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ isoptionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl ornaphthalen-1-yl; e) each R⁵ is independently selected from H, halo,C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl,R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ isH, halo; and g) Z is a bond or a substituted or unsubstituted C₁-C₄alkylene group.
 4. A compound of the formula

wherein: a) W¹ is a bond or a C₁-C₄ alkylene group; b) R¹¹ is aryl,aryloxy, aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R¹¹ isoptionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂alkoxy, or wherein R¹¹ is H; c) Y¹ is a bond, C₁-C₃ alkylene or —O-C₁-C₂alkylene; d) each R¹³ is independently selected from H, halo, N₂O, C₁-C₄alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, phenyl, phenoxy, benzyl,benzyloxy, p-halophenyl, p-halobenzyl, p-halophenoxy andp-halobenzyloxy; and e) B² is selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 5. Acompound of the formula

wherein: a) W¹ is C₁-C₃ alkylene; b) R¹¹ is aryl, aryloxy,aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R¹¹ isoptionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂alkoxy, or R¹¹ is H; c) Y² is a bond, C₁-C₃ alkylene; d) each R¹⁴ isindependently selected from H, halo, C₁-C₂ alkyl C₁-C₂ alkoxy, C₁-C₂haloalkyl; and e) B² is selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 6. Acompound of the formula

wherein: a) independently, each Q is a bond or a methylene group; b)each R¹⁵ is independently selected from H, halo, N₂O, C₁-C₄ alkyl, C₁-C₂alkoxy, C₁-C₂ haloalkyl and CONHCH₃; R¹⁶ is H or C₁-C₂ alkyl; and c) B²is selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 7. Acompound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ isH, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substitutedwith 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical,aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, whereinR^(4a) is optionally substituted with 1-3 R⁵; e) each R⁵ isindependently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy,NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; and g) Z is a bond or asubstituted or unsubstituted C₁-C₄ alkylene group.
 8. A pharmaceuticalcomposition, comprising a) a compound of the formula

wherein: (i) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; (ii) R² is H or C₁-C₄ alkyl; (iii) R³is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionallysubstituted with 1-3 R⁵; (iv) R^(4a) is carbocylic radical, heterocyclicradical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene,aryl-NHC(O)—, wherein R^(4a) is optionally substituted with 1-3 R⁵; (v)each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy,R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; (vi) R⁶ is H, halo;(vii) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylenegroup; (viii) and B² is selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof; andb) a pharmaceutically acceptable carrier.
 9. The pharmaceuticalcomposition of claim 8, further comprising a therapeutically effectiveamount of one or more other HIV treatment agents selected from (a) anHIV protease inhibitor, (b) a nucleoside reverse transcriptaseinhibitor, (c) a non-nucleoside reverse transcriptase inhibitor, (d) anHIV-entry inhibitor, or (e) an immunomodulator, or a combinationthereof.
 10. A method of inhibiting HIV integrase which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount a compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ isH, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substitutedwith 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical,aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, whereinR^(4a) is optionally substituted with 1-3 R⁵; e) each R⁵ isindependently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy,NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) Z is a bond or asubstituted or unsubstituted C₁-C₄ alkylene group; and h) B² is selectedfrom

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 11. Amethod of for treating an HIV infection, in a patient in need thereof,comprising the administration to said patient of a therapeuticallyeffective amount a compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ isH, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substitutedwith 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical,aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, whereinR^(4a) is optionally substituted with 1-3 R⁵; e) each R⁵ isindependently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy,NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) Z is a bond or asubstituted or unsubstituted C₁-C₄ alkylene group; and h) B² is selectedfrom

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 12. Amethod of prophylactically or therapeutically treating AIDS or ARC, in apatient in need thereof, comprising the administration to said patientof a therapeutically effective amount a compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclicradical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—,wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ isH, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substitutedwith 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical,aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, whereinR^(4a) is optionally substituted with 1-3 R⁵; e) each R⁵ isindependently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy,NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) Z is a bond or asubstituted or unsubstituted C₁-C₄ alkylene group; and h) B² is selectedfrom

or a pharmaceutically acceptable salt, solvate or prodrug thereof.